Secreted and transmembrane polypeptides and nucleic acids encoding the same

ABSTRACT

The present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

RELATED APPLICATIONS

This application is a continuation of, and claims priority under 35 USC §120 to, U.S. application Ser. No. 09/665,350 filed Sep. 18, 2000, which is a continuation of, and claims priority under 35 USC §120 to, PCT Application PCT/US00/04414 filed Feb. 22, 2000, which is a continuation-in-part of, and claims priority under 35 USC §120 to, PCT Application PCT/US98/19437 filed Sep. 17, 1998, which is a continuation-in-part of, and claims priority under 35 USC §120 to, PCT Application PCT/US98/19330 filed Sep. 16, 1998 which claims priority under 35 USC §119 to U.S. Provisional Application No. 60/088,026 filed Jun. 4, 1998, to U.S. Provisional Application No. 60/066,770 filed Nov. 24, 1997, and to U.S. Provisional Application No. 60/065,186 filed Nov. 12, 1997.

FIELD OF THE INVENTION

The present invention relates generally to the identification and isolation of novel DNA and to the recombinant production of novel polypeptides.

BACKGROUND OF THE INVENTION

Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.

Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesin molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.

Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immunoadhesins, for instance, can be employed as therapeutic agents to block receptor-ligand interactions. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.

Efforts are being undertaken by both industry and academia to identify new, native receptor or membrane-bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor or membrane-bound proteins.

1. PRO211 and PRO217

Epidermal growth factor (EGF) is a conventional mitogenic factor that stimulates the proliferation of various types of cells including epithelial cells and fibroblasts. EGF binds to and activates the EGF receptor (EGFR), which initiates intracellular signaling and subsequent effects. The EGFR is expressed in neurons of the cerebral cortex, cerebellum, and hippocampus in addition to other regions of the central nervous system (CNS). In addition, EGF is also expressed in various regions of the CNS. Therefore, EGF acts not only on mitotic cells, but also on postmitotic neurons. In fact, many studies have indicated that EGF has neurotrophic or neuromodulatory effects on various types of neurons in the CNS. For example, EGF acts directly on cultured cerebral cortical and cerebellar neurons, enhancing neurite outgrowth and survival. On the other hand, EGF also acts on other cell types, including septal cholinergic and mesencephalic dopaminergic neurons, indirectly through glial cells. Evidence of the effects of EGF on neurons in the CNS is accumulating, but the mechanisms of action remain essentially unknown. EGF-induced signaling in mitotic cells is better understood than in postmitotic neurons. Studies of cloned pheochromocytoma PC12 cells and cultured cerebral cortical neurons have suggested that the EGF-induced neurotrophic actions are mediated by sustained activation of the EGFR and mitogen-activated protein kinase (MAPK) in response to EGF. The sustained intracellular signaling correlates with the decreased rate of EGFR down-regulation, which might determine the response of neuronal cells to EGF. It is likely that EGF is a multi-potent growth factor that acts upon various types of cells including mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of the gastrointestinal system, kidney, pancreas, thyroid gland, pituitary gland, and the nervous system, and is found in body fluids such as saliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid, prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, Peptides 12: 653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains an intrinsic tyrosine kinase. Stoscheck et al., J. Cell Biochem. 31: 135-152 (1986). EGF is believed to function by binding to the extracellular portion of its receptor which induces a transmembrane signal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGF-like domain has revealed the presence of six conserved cysteine residues which cross-bind to create three peptide loops, Savage et at., J. Biol. Chem. 248: 7669-7672 (1979). It is now generally known that several other peptides can react with the EGF receptor which share the same generalized motif. Non isolated peptides having this motif include TGF-α amphiregulin, schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growth factors and certain virally encoded peptides (e.g., Vaccinia virus, Reisner, Nature 313: 801-803 (1985), Shope fibroma virus, Chang et al., Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, Porter and Archard, J. Gen. Virol. 68: 673-682 (1987), and Myxoma virus, Upton et at., J. Virol. 61: 1271-1275 (1987), Prigent and Lemoine, Prog. Growth Factor Res. 4:1-24 1992).

EGF-like domains are not confined to growth factors but have been observed in a variety of cell-surface and extracellular proteins which have interesting properties in cell adhesion, protein-protein interaction and development, Laurence and Gusterson, Tumor Biol. 11: 229-261 (1990). These proteins include blood coagulation factors (factors VI, IX, X, XII, protein C, protein S, protein Z, tissue plasminogen activator, urokinase), extracellular matrix components (laminin, cytotactin, entactin), cell surface receptors (LDL receptor, thrombomodulin receptor) and immunity-related proteins (complement C1r, uromodulin).

Even more interesting, the general structure pattern of EGF-like precursors is preserved through lower organisms as well as in mammalian cells. A number of genes with developmental significance have been identified in invertebrates with EGF-like repeats. For example, the notch gene of Drosophila encodes 36 tandemly arranged 40 amino acid repeats which show homology to EGF, Wharton et al., Cell 43: 557-581 (1985). Hydropathy plots indicate a putative membrane spanning domain, with the EGF-related sequences being located on the extracellular side of the membrane. Other homeotic genes with EGF-like repeats include Delta, 95F and 5ZD which were identified using probes based on Notch, and the nematode gene Lin-12 which encodes a putative receptor for a developmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions, Konturek et al., Eur. J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including the treatment of necrotizing enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration gastrointestinal ulcerations and congenital microvillus atrophy, Guglietta and Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50 (1995). Additionally, EGF has been implicated in hair follicle differentiation; du Cros, J. Invest. Dermatol. 101 (1 Suppl.), 106S-113S (1993), Hillier, Clin. Endocrinol. 33(4), 427-28 (1990); kidney function, Hamm et al., Semin. Nephrol. 13(1): 109-15 (1993), Harris, Am. J. Kidney Dis. 17(6): 627-30 (1991); tear fluid, van Setten et al., Int. Ophthalmol 15(6); 359-62(1991); vitamin K mediated blood coagulation, Stenflo et al., Blood 78(7): 1637-51(1991). EGF is also implicated various skin disease characterized by abnormal keratinocyte differentiation, e.g., psoriasis, epithelial cancers such as squamous cell carcinomas of the lung, epidermoid carcinoma of the vulva and gliomas. King et al., Am. J. Med. Sci. 296: 154-158 (1988).

Of great interest is mounting evidence that genetic alterations in growth factors signaling pathways are closely linked to developmental abnormalities and to chronic diseases including cancer. Aaronson, Science 254: 1146-1153 (1991). For example, c-erb-2 (also known as HER-2), a proto-oncogene with close structural similarity to EGF receptor protein, is overexpressed in human breast cancer. King et al., Science 229: 974-976 (1985); Gullick, Hormones and their actions, Cooke et al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

We herein describe the identification and characterization of novel polypeptides having homology to EGF, wherein those polypeptides are herein designated PRO211 and PRO217.

2. PRO230

Nephritis is a condition characterized by inflammation of the kidney affecting the structure and normal function of the kidney. This condition can be chronic or acute and is generally caused by infection, degenerative process or vascular disease. In all cases, early detection is desirable so that the patient with nephritis can begin treatment of the condition.

An approach to detecting nephritis is to determine the antigens associated with nephritis and antibodies thereto. In rabbit, a tubulointerstitial nephritis antigen (TIN-ag) has been reported in Nelson, T. R., et al., J. Biol. Chem., 270(27):16265-70 (July 1995) (GENBANK/U24270). This study reports that the rabbit TIN-ag is a basement membrane glycoprotein having a predicted amino acid sequence which has a carboxyl-terminal region exhibiting 30% homology with human preprocathepsin B, a member of the cystein proteinase family of proteins. It is also reported that the rabbit TIN-ag has a domain in the amino-terminal region containing an epidermal growth factor-like motif that shares homology with laminin A and S chains, alpha 1 chain of type I collagen, von Willebrand's factor and mucin, indicating structural and functional similarities. Studies have also been conducted in mice. However, it is desirable to identify tubulointerstitial nephritis antigens in humans to aid in the development of early detection methods and treatment of nephritis.

Proteins which have homology to tubulointerstitial nephritis antigens are of particular interest to the medical and industrial communities. Often, proteins having homology to each other have similar function. It is also of interest when proteins having homology do not have similar functions, indicating that certain structural motifs identify information other than function, such as locality of function. We herein describe the identification and characterization of a novel polypeptide, designated herein as PRO230, which has homology to tubulointerstitial nephritis antigens.

3. PRO232

Stem cells are undifferentiated cells capable of (a) proliferation, (b) self maintenance, (c) the production of a large number of differentiated functional progeny, (d) regeneration of tissue after injury and/or (e) a flexibility in the use of these options. Stem cells often express cell surface antigens which are capable of serving as cell specific markers that can be exploited to identify stem cells, thereby providing a means for identifying and isolating specific stem cell populations.

Having possession of different stem cell populations will allow for a number of important applications. For example, possessing a specific stem cell population will allow for the identification of growth factors and other proteins which are involved in their proliferation and differentiation. In addition, there may be as yet undiscovered proteins which are associated with (1) the early steps of dedication of the stem cell to a particular lineage, (2) prevention of such dedication, and (3) negative control of stem cell proliferation, all of which may be identified if one has possession of the stem cell population. Moreover, stem cells are important and ideal targets for gene therapy where the inserted genes promote the health of the individual into whom the stem cells are transplanted. Finally, stem cells may play important roles in transplantation of organs or tissues, for example liver regeneration and skin grafting.

Given the importance of stem cells in various different applications, efforts are currently being undertaken by both industry and academia to identify new, native stem cell antigen proteins so as to provide specific cell surface markers for identifying stem cell populations as well as for providing insight into the functional roles played by stem cell antigens in cell proliferation and differentiation. We herein describe the identification and characterization of novel polypeptides having homology to a stem cell antigen, wherein those polypeptides are herein designated as PRO232 polypeptides.

4. PRO187

Growth factors are molecular signals or mediators that enhance cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. However, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects. For example, transforming growth factor (TGF-β) is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissue, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.

The physiological effect of growth stimulation or inhibition by growth factors depends upon the state of development and differentiation of the target tissue. The mechanism of local cellular regulation by classical endocrine molecules involves comprehends autocrine (same cell), juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways. Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression. The effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.

FGF-8 is a member of the fibroblast growth factors (FGFs) which are a family of heparin-binding, potent mitogens for both normal diploid fibroblasts and established cell lines, Gospodarowicz et al. (1984), Proc. Nat. Acad. Sci. USA 81:6963. The FGF family comprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have two conserved cysteine residues and share 30-50% sequence homology at the amino acid level. These factors are mitogenic for a wide variety of normal diploid mesoderm-derived and neural crest-derived cells, including granulosa cells, adrenal cortical cells, chondrocytes, myoblasts, corneal and vascular endothelial cells (bovine or human), vascular smooth muscle cells, lens, retina and prostatic epithelial cells, oligodendrocytes, astrocytes, chrondocytes, myoblasts and osteoblasts.

Fibroblast growth factors can also stimulate a large number of cell types in a non-mitogenic manner.

These activities include promotion of cell migration into wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird & Bohlen, Handbook of Exp. Pharmacol. 95(1): 369-418, Springer, (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like. For example, fibroblast growth factors have been suggested to minimize myocardium damage in heart disease and surgery (U.S. Pat. No. 4,378,347).

FGF-8, also known as androgen-induced growth factor (AIGF), is a 215 amino acid protein which shares 30-40% sequence homology with the other members of the FGF family. FGF-8 has been proposed to be under androgenic regulation and induction in the mouse mammary carcinoma cell line SC3. Tanaka et al., Proc. Natl. Acad. Sci. USA 89: 8928-8932 (1992); Sato et al., J. Steroid Biochem. Molec. Biol. 47: 91-98 (1993). As a result, FGF-8 may have a local role in the prostate, which is known to be an androgen-responsive organ. FGF-8 can also be oncogenic, as it displays transforming activity when transfected into NIH-3T3 fibroblasts. Kouhara et al., Oncogene 9 455-462 (1994). While FGF-8 has been detected in heart, brain, lung, kidney, testis, prostate and ovary, expression was also detected in the absence of exogenous androgens. Schmitt et al., J. Steroid Biochem. Mol. Biol. 57 (3-4): 173-78 (1996).

FGF-8 shares the property with several other FGFs of being expressed at a variety of stages of murine embryogenesis, which supports the theory that the various FGFs have multiple and perhaps coordinated roles in differentiation and embryogenesis. Moreover, FGF-8 has also been identified as a protooncogene that cooperates with Wnt-1 in the process of mammary tumorigenesis (Shackleford et al., Proc. Natl. Acad. Sci. USA 90, 740-744 (1993); Heikinheimo et al., Mech. Dev. 48: 129-138 (1994)).

In contrast to the other FGFs, FGF-8 exists as three protein isoforms, as a result of alternative splicing of the primary transcript. Tanaka et al., supra. Normal adult expression of FGF-8 is weak and confined to gonadal tissue, however northern blot analysis has indicated that FGF-8 mRNA is present from day 10 through day 12 or murine gestation, which suggests that FGF-8 is important to normal development. Heikinheimo et al., Mech Dev. 48(2): 129-38 (1994). Further in situ hybridization assays between day 8 and 16 of gestation indicated initial expression in the surface ectoderm of the first bronchial arches, the frontonasal process, the forebrain and the midbrain-hindbrain junction. At days 10-12, FGF-8 was expressed in the surface ectoderm of the forelimb and hindlimb buds, the nasal its and nasopharynx, the infundibulum and in the telencephalon, diencephalon and metencephalon. Expression continues in the developing hindlimbs through day 13 of gestation, but is undetectable thereafter. The results suggest that FGF-8 has a unique temporal and spatial pattern in embryogenesis and suggests a role for this growth factor in multiple regions of ectodermal differentiation in the post-gastrulation embryo.

We herein describe the identification of novel poypeptides having homology to FGF-8, wherein those polypeptides are herein designated PRO187 polypeptides.

5. PRO265

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats. Another protein of particular interest which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Other studies reporting on the biological functions of proteins having leucine-rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December) 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation (decorin binding to transforming growth factor-β involvement for treatment for cancer, wound healing and scarring). Also of particular interest is fibromodulin and its use to prevent or reduce dermal scarring. A study of fibromodulin is found in U.S. Pat. No. 5,654,270 to Ruoslahti, et al.

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and homology to known proteins having leucine rich repeats such as fibromodulin, the SLIT protein and platelet glycoprotein V. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound proteins having leucine rich repeats. We herein describe the identification and characterization of novel polypeptides having homology to fibromodulin, herein designated as PRO265 polypeptides.

6. PRO219

Human matrilin-2 polypeptide is a member of the von Willebrand factor type A-like module superfamily. von Willebrand factor is a protein which plays an important role in the maintenence of hemostasis. More specifically, von Willebrand factor is a protein which is known to participate in platelet-vessel wall interactions at the site of vascular injury via its ability to interact and form a complex with Factor VIII. The absence of von Willebrand factor in the blood causes an abnormality with the blood platelets that prevents platelet adhesion to the vascular wall at the site of the vascular injury. The result is the propensity for brusing, nose bleeds, intestinal bleeding, and the like comprising von Willebrand's disease.

Given the physiological importance of the blood clotting factors, efforts are currently being undertaken by both industry and academia to identify new, native proteins which may be involved in the coagulation process. We herein describe the identification of a novel full-length polypeptide which possesses homology to the human matrilin-2 precursor polypeptide.

7. PRO246

The cell surface protein HCAR is a membrane-bound protein that acts as a receptor for subgroup C of the adenoviruses and subgroup B of the coxsackieviruses. Thus, HCAR may provide a means for mediating viral infection of cells in that the presence of the HCAR receptor on the cellular surface provides a binding site for viral particles, thereby facilitating viral infection.

In light of the physiological importance of membrane-bound proteins and specifically those which serve a cell surface receptor for viruses, efforts are currently being undertaken by both industry and academia to identify new, native membrane-bound receptor proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe a novel membrane-bound polypeptide (designated herein as PRO246) having homology to the cell surface protein HCAR and to various tumor antigens including A33 and carcinoembryonic antigen, wherein this polypeptide may be a novel cell surface virus receptor or tumor antigen.

8. PRO228

There are a number of known seven transmembrane proteins and within this family is a group which includes CD97 and EMR1. CD97 is a seven-span transmembrane receptor which has a cellular ligand, CD55, DAF. Hamann, et al., J. Exp. Med. (U.S.), 184(3):1189 (1996). Additionally, CD97 has been reported as being a dedifferentiation marker in human thyroid carcinomas and as associated with inflammation. Aust, et al., Cancer Res. (U.S.), 57(9):1798 (1997); Gray, et al., J. Immunol. (U.S.), 157(12):5438 (1996). CD97 has also been reported as being related to the secretin receptor superfamily, but unlike known members of that family, CD97 and EMR1 have extended extracellular regions that possess several EGF domains at the N-terminus. Harmann, et al., Genomics, 32(1):144 (1996); Harmann, et al., J. Immunol., 155(4):1942 (1995). EMR1 is further described in Lin, et al., Genomics, 41(3):301 (1997) and Baud, et al., Genomics, 26(2):334 (1995). While CD97 and EMR1 appear to be related to the secretin receptors, a known member of the secretin family of G protein-coupled receptors includes the alpha-latroxin receptor, latrophilin, which has been described as calcium independent and abundant among neuronal tissues. Lelianova, et al., J. Biol. Chem., 272(34), 21504 (1997); Davletov, et al., J. Biol. Chem. (U.S.), 271(38):23239 (1996). Both members of the secretin receptor superfamily and non-members which are related to the secretin receptor superfamily, or CRF and calcitonin receptors are of interest. In particular, new members of these families, identified by their homology to known proteins, are of interest.

Efforts are being undertaken by both industry and academia to identify new membrane-bound receptor proteins, particularly transmembrane proteins with EGF repeats and large N-terminus which may belong to the family of seven-transmembrane proteins of which CD97 and EMR1 are members. We herein describe the identification and charactization of novel polypeptides having homology to CD97 and EMR1, designated herein as PRO228 polypeptides.

9. PRO533

Growth factors are molecular signals or mediators that enhance cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. However, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects. For example, transforming growth factors (TGF-β) is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissues, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.

The physiological effect of growth stimulation or inhibition by growth factors depends upon the state of development and differentiation of the target tissue. The mechanism of local cellular regulation by classical endocrine molecules comprehends autocrine (same cell), juxtacrine (neighbor cell), and paracrine (adjacent cell) pathways. Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression. The effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.

Fibroblast growth factors (FGFs) are a family of heparin-binding, potent mitogens for both normal diploid fibroblasts and established cell lines, Godpodarowicz, D. et al. (1984), Proc. Natl. Acad. Sci. USA 81: 6983. the FGF family comprises acidic FGF (FGF-1), basic FGF (FGF-2), INT-2 (FGF-3), K-FGF/HST (FGF-4), FGF-5, FGF-6, KGF (FGF-7), AIGF (FGF-8) among others. All FGFs have two conserved cysteine residues and share 30-50% sequence homology at the amino acid level. These factors are mitogenic for a wide variety of normal diploid mesoderm-derived and neural crest-derived cells, inducing granulosa cells, adrenal cortical cells, chrondocytes, myoblasts, corneal and vascular endothelial cells (bovine or human), vascular smooth muscle cells, lens, retina and prostatic epithelial cells, oligodendrocytes, astrocytes, chrondocytes, myoblasts and osteoblasts.

Fibroblast growth factors can also stimulate a large number of cell types in a non-mitogenic manner. These activities include promotion of cell migration into a wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird, A. & Bohlen, P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like. For example, fibroblast growth factors, have been suggested to minimize myocardium damage in heart disease and surgery (U.S. Pat. No. 4,378,437).

We herein describe the identification and characterization of novel polypeptides having homology to FGF, herein designated PRO533 polypeptides.

10. PRO245

Some of the most important proteins involved in the above described regulation and modulation of cellular processes are the enzymes which regulate levels of protein phosphorylation in the cell. For example, it is known that the transduction of signals that regulate cell growth and differentiation is regulated at least in part by phosphorylation and dephosphorylation of various cellular proteins. The enzymes that catalyze these processes include the protein kinases, which function to phosphorylate various cellular proteins, and the protein phosphatases, which function to remove phosphate residues from various cellular proteins. The balance of the level of protein phosphorylation in the cell is thus mediated by the relative activities of these two types of enzymes.

Although many protein kinase enzymes have been identified, the physiological role played by many of these catalytic proteins has yet to be elucidated. It is well known, however, that a number of the known protein kinases function to phosphorylate tyrosine residues in proteins, thereby leading to a variety of different effects. Perhaps most importantly, there has been a great deal of interest in the protein tyrosine kinases since the discovery that many oncogene products and growth factors possess intrinsic protein tyrosine kinase activity. There is, therefore, a desire to identify new members of the protein tyrosine kinase family.

Given the physiological importance of the protein kinases, efforts are being undertaken by both industry and academia to identify new, native kinase proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel kinase proteins. We herein describe the identification and characterization of novel polypeptides having homology to tyrosine kinase proteins, designated herein as PRO245 polypeptides.

11. PRO220, PRO221 and PRO227

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats. Another protein of particular interest which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Other studies reporting on the biological functions of proteins having leucine-rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation (decorin binding to transforming growth factorβ involvement for treatment for cancer, wound healing and scarring).

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and homology to known proteins having leucine rich repeats such as the SLIT protein and platelet glycoprotein V.

12. PRO258

Immunoglobulins are antibody molecules, the proteins that function both as receptors for antigen on the B-cell membrane and as the secreted products of the plasma cell. Like all antibody molecules, immunoglobulins perform two major functions: they bind specifically to an antigen and they participate in a limited number of biological effector functions. Therefore, new members of the Ig superfamily are always of interest. Molecules which act as receptors by various viruses and those which act to regulate immune function are of particular interest. Also of particular interest are those molecules which have homology to known Ig family members which act as virus receptors or regulate immune function. Thus, molecules having homology to poliovirus receptors, CRTAM and CD166 (a ligand for lymphocyte antigen CD6) are of particular interest.

Extracellular and membrane-bound proteins play important roles in the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment, usually at a membrane-bound receptor protein.

We herein describe the identification and characterization of novel polypeptides having homology to CRTAM, designated herein as PRO258 polypeptides.

13. PRO266

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglobular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats. Another protein of particular interest which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Other studies reporting on the biological functions of proteins having leucine-rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation (decorin binding to transforming growth factorβ involvement for treatment for cancer, wound healing and scarring).

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions, neuronal development and adhesin molecules. Of particular interest are those proteins having leucine rich repeats and homology to known proteins having leucine rich repeats such as the SLIT protein. We herein describe novel polypeptides having homology to SLIT, designated herein as PRO266 polypeptides.

14. PRO269

Thrombomodulin binds to and regulates the activity of thrombin. It is important in the control of blood coagulation. Thrombomodulin functions as a natural anticoagulant by accelerating the activation of protein C by thrombin. Soluble thrombomodulin may have therapeutic use as an antithrombotic agent with reduced risk for hemorrhage as compared with heparin. Thrombomodulin is a cell surface trans-membrane glycoprotein, present on endothelial cells and platelets. A smaller, functionally active form of thrombomodulin circulates in the plasma and is also found in urine. (In Haeberli, A., Human Protein Data, VCH Oub., N.Y., 1992). Peptides having homology to thrombomodulin are particularly desirable.

We herein describe the identification and characterization of novel polypeptides having homology to thrombomodulin, designated herein as PRO269 polypeptides.

15. PRO287

Procollagen C-proteinase enhancer protein binds to and enhances the activity of bone morphogenic protein “BMP1”/procollagen C-proteinase (PCP). It plays a role in extracellular matrix deposition. BMP1 proteins may be used to induce bone and/or cartilage formation and in wound healing and tissue repair. Therefore, procollagen C-proteinase enhancer protein, BMP1 and proteins having homology thereto, are of interest to the scientific and medical communities.

We herein describe the identification and characterization of novel polypeptides having homology to procollagen C-proteinase enhancer protein precursor and procollagen C-proteinase enhancer protein, designated herein as PRO287 polypeptides.

16. PRO214

Growth factors are molecular signals or mediators that enhances cell growth or proliferation, alone or in concert, by binding to specific cell surface receptors. However, there are other cellular reactions than only growth upon expression to growth factors. As a result, growth factors are better characterized as multifunctional and potent cellular regulators. Their biological effects include proliferation, chemotaxis and stimulation of extracellular matrix production. Growth factors can have both stimulatory and inhibitory effects. For example, transforming growth factor β (TGF-β) is highly pleiotropic and can stimulate proliferation in some cells, especially connective tissue, while being a potent inhibitor of proliferation in others, such as lymphocytes and epithelial cells.

The physiological effect of growth stimulation or inhibition by growth factors depends upon the state of development and differentiation of the target tissue. The mechanism of local cellular regulation by classical endocrine molecules involves comprehends autocrine (same cell), juxtacrine (neighbor cell), and paracrine (adjacent cells) pathways. Peptide growth factors are elements of a complex biological language, providing the basis for intercellular communication. They permit cells to convey information between each other, mediate interaction between cells and change gene expression. The effect of these multifunctional and pluripotent factors is dependent on the presence or absence of other peptides.

Epidermal growth factor (EGF) is a conventional mitogenic factor that stimulates the proliferation of various types of cells including epithelial cells and fibroblasts. EGF binds to and activates the EGF receptor (EGFR), which initiates intracellular signaling and subsequent effects. The EGFR is expressed in neurons of the cerebral cortex, cerebellum, and hippocampus in addition to other regions of the central nervous system (CNS). In addition, EGF is also expressed in various regions of the CNS. Therefore, EGF acts not only on mitotic cells, but also on postmitotic neurons. In fact, many studies have indicated that EGF has neurotrophic or neuromodulatory effects on various types of neurons in the CNS. For example, EGF acts directly on cultured cerebral cortical and cerebellar neurons, enhancing neurite outgrowth and survival. On the other hand, EGF also acts on other cell types, including septal cholinergic and mesencephalic dopaminergic neurons, indirectly through glial cells. Evidence of the effects of EGF on neurons in the CNS is accumulating, but the mechanisms of action remain essentially unknown. EGF-induced signaling in mitotic cells is better understood than in postmitotic neurons. Studies of cloned pheochromocytoma PC12 cells and cultured cerebral cortical neurons have suggested that the EGF-induced neurotrophic actions are mediated by sustained activation of the EGFR and mitogen-activated protein kinase (MAPK) in response to EGF. The sustained intracellular signaling correlates with the decreased rate of EGFR down-regulation, which might determine the response of neuronal cells to EGF. It is likely that EGF is a multi-potent growth factor that acts upon various types of cells including mitotic cells and postmitotic neurons.

EGF is produced by the salivary and Brunner's glands of the gastrointestinal system, kidney, pancreas, thyroid gland, pituitary gland, and the nervous system, and is found in body fluids such as saliva, blood, cerebrospinal fluid (CSF), urine, amniotic fluid, prostatic fluid, pancreatic juice, and breast milk, Plata-Salaman, CR Peptides 12: 653-663 (1991).

EGF is mediated by its membrane specific receptor, which contains an intrinsic tyrosine kinase. Stoscheck C M et al., J. Cell Biochem. 31: 135-152 (1986). EGF is believed to function by binding to the extracellular portion of its receptor which induces a transmembrane signal that activates the intrinsic tyrosine kinase.

Purification and sequence analysis of the EGE-like domain has revealed the presence of six conserved cysteine residues which cross-bind to create three peptide loops, Savage C R et at., J. Biol. Chem. 248: 7669-7672 (1979). It is now generally known that several other peptides can react with the EGF receptor which share the same generalized motif. Non isolated peptides having this motif include TGF-a, amphiregulin, schwannoma-derived growth factor (SDGF), heparin-binding EGF-like growth factors and certain virally encoded peptides (e.g., Vaccinia virus, Reisner A H, Nature 313: 801-803 (1985), Shope fibroma virus, Chang W., et al., Mol Cell Biol. 7: 535-540 (1987), Molluscum contagiosum, Porter C D & Archard L C, J. Gen. Virol. 68: 673-682 (1987), and Myxoma virus, Upton C et al., J. Virol. 61: 1271-1275 (1987). Prigent S A & Lemoine N. R., Prog. Growth Factor Res. 4:1-24 (1992).

EGF-like domains are not confined to growth factors but have been observed in a variety of cell-surface and extracellular proteins which have interesting properties in cell adhesion, protein-protein interaction and development, Laurence D J R & Gusterson B A, Tumor Biol. 11: 229-261 (1990). These proteins include blood coagulation factors (factors VI, IX, X, XII, protein C, protein S, protein Z, tissue plasminogen activator, urokinase), extracellular matrix components (laminin, cytotactin, entactin), cell surface receptors (LDL receptor, thrombomodulin receptor) and immunity-related proteins (complement C1r, uromodulin).

Even more interesting, the general structure pattern of EGF-like precursors is preserved through lower organisms as well as in mammalian cells. A number of genes with developmental significance have been identified in invertebrates with EGF-like repeats. For example, the notch gene of Drosophila encodes 36 tandemly arranged 40 amino acid repeats which show homology to EGF, Wharton W et al., Cell 43: 557-581 (1985). Hydropathy plots indicate a putative membrane spanning domain, with the EGF-related sequences being located on the extracellular side of the membrane. Other homeotic genes with EGF-like repeats include Delta, 95F and 5ZD which were identified using probes based on Notch, and the nematode gene Lin-12 which encodes a putative receptor for a developmental signal transmitted between two specified cells.

Specifically, EGF has been shown to have potential in the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions, Konturek, P C et al., Eur. J. Gastroenterol Hepatol. 7 (10), 933-37 (1995), including the treatment of necrotizing enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration gastrointestinal ulcerations and congenital microvillus atrophy, A. Guglietta & P B Sullivan, Eur. J. Gastroenterol Hepatol, 7(10), 945-50 (1995). Additionally, EGF has been implicated in hair follicle differentiation; C. L. du Cros, J. Invest. Dermatol. 101 (1 Suppl.), 106S-113S (1993), S G Hillier, Clin. Endocrinol. 33(4), 427-28 (1990); kidney function, L. L. Hamm et al., Semin. Nephrol. 13 (1): 109-15 (1993), R C Harris, Am. J. Kidney Dis. 17(6): 627-30 (1991); tear fluid, G B van Setten et al., Int. Ophthalmol 15(6); 359-62(1991); vitamin K mediated blood coagulation, J. Stenflo et al., Blood 78(7): 1637-51 (1991). EGF is also implicated various skin disease characterized by abnormal keratinocyte differentiation, e.g., psoriasis, epithelial cancers such as squamous cell carcinomas of the lung, epidermoid carcinoma of the vulva and gliomas. King, L E et al., Am. J. Med. Sci. 296: 154-158 (1988).

Of great interest is mounting evidence that genetic alterations in growth factors signaling pathways are closely linked to developmental abnormalities and to chronic diseases including cancer. Aaronson S A, Science 254: 1146-1153 (1991). For example, c-erb-2 (also known as HER-2), a proto-oncogene with close structural similarity to EGF receptor protein, is overexpressed in human breast cancer. King et al., Science 229: 974-976 (1985); Gullick, W J, Hormones and their actions, Cooke B A et al., eds, Amsterdam, Elsevier, pp 349-360 (1986).

17. PRO317

The TGF-β supergene family, or simply TGF-β superfamily, a group of secreted proteins, includes a large number of related growth and differentiation factors expressed in virtually all phyla. Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their multifunctional cytokine effects. Kolodziejczyk and Hall, Biochem. Cell. Biol., 74: 299-314 (1996); Attisano and Wrana, Cytokine Growth Factor Rev., 7: 327-339 (1996); and Hill, Cellular Signaling, 8: 533-544 (1996).

Members of this family include five distinct forms of TGF-β (Sporn and Roberts, in Peptide Growth Factors and Their Receptors, Sporn and Roberts, eds. (Springer-Verlag: Berlin, 1990) pp. 419-472), as well as the differentiation factors vg1 (Weeks and Melton, Cell, 51: 861-867 (1987)) and DPP-C polypeptide (Padgett et al., Nature, 325: 81-84 (1987)), the hormones activin and inhibin (Mason et al., Nature 318: 659-663 (1985); Mason et al., Growth Factors, 1: 77-88 (1987)), the Mullerian-inhibiting substance (MIS) (Cate et al., Cell, 45: 685-698 (1986)), the bone morphogenetic proteins (BMPs) (Wozney et al., Science, 242: 1528-1534 (1988); PCT WO 88/00205 published Jan. 14, 1988; U.S. Pat. No. 4,877,864 issued Oct. 31, 1989), the developmentally regulated proteins Vgr-1 (Lyons et al., Proc. Natl. Acad. Sci. USA. 86: 45544558 (1989)) and Vgr-2 (Jones et al., Molec. Endocrinol., 6: 1961-1968 (1992)), the mouse growth differentiation factor (GDF), such as GDF-3 and GDF-9 (Kingsley, Genes Dev., 8: 133-146 (1994); McPherron and Lee, J. Biol. Chem., 268: 3444-3449 (1993)), the mouse lefty/Stra1 (Meno et al., Nature, 381: 151-155 (1996); Bouillet et al., Dev. Biol., 170: 420-433 (1995)), glial cell line-derived neurotrophic factor (GDNF) (Lin et al., Science, 260: 1130-1132 (1993), neurturin (Kotzbauer et al., Nature, 384: 467-470 (1996)), and endometrial bleeding-associated factor (EBAF) (Kothapalli et al., J. Clin. Invest., 99: 2342-2350 (1997)). The subset BMP-2A and BMP-2B is approximately 75% homologous in sequence to DPP-C and may represent the mammalian equivalent of that protein.

The proteins of the TGF-β superfamily are disulfide-linked homo- or heterodimers encoded by larger precursor polypeptide chains containing a hydrophobic signal sequence, a long and relatively poorly conserved N-terminal pro region of several hundred amino acids, a cleavage site (usually polybasic), and a shorter and more highly conserved C-terminal region. This C-terminal region corresponds to the processed mature protein and contains approximately 100 amino acids with a characteristic cysteine motif, i.e., the conservation of seven of the nine cysteine residues of TGF-β among all known family members. Although the position of the cleavage site between the mature and pro regions varies among the family members, the C-terminus of all of the proteins is in the identical position, ending in the sequence Cys-X-Cys-X, but differing in every case from the TGF-β consensus C-terminus of Cys-Lys-Cys-Ser. Sporn and Roberts, 1990, supra.

There are at least five forms of TGF-β currently identified, TGF-β1, TGF-β2, TGF-β3, TGF-β4, and TGF-β5. The activated form of TGF-β1 is a homodimer formed by dimerization of the carboxy-terminal 112 amino acids of a 390 amino acid precursor. Recombinant TGF-β1 has been cloned (Derynck et al., Nature, 316:701-705 (1985)) and expressed in Chinese hamster ovary cells (Gentry et al., Mol. Cell. Biol. 7: 3418-3427 (1987)). Additionally, recombinant human TGF-β2 (deMartin et al., EMBO J., 6: 3673 (1987)), as well as human and porcine TGF-β3 (Derynck et al., EMBO J., 7: 3737-3743 (1988); ten Dijke et al., Proc. Natl. Acad. Sci. U.S.A., 85: 4715 (1988)) have been cloned. TGF-β2 has a precursor form of 414 amino acids and is also processed to a homodimer from the carboxy-terminal 112 amino acids that shares approximately 70% homology with the active form of TGF-β1 (Marquardt et al., J. Biol. Chem., 262: 12127 (1987)). See also EP 200,341; 169,016; 268,561; and 267,463; U.S. Pat. No. 4,774,322; Cheifetz et al., Cell, 48: 409-415 (1987); Jakowlew et al., Molecular Endocrin., 2: 747-755 (1988); Derynck et al., J. Biol. Chem., 261: 4377-4379 (1986); Sharples et al., DNA, 6: 239-244 (1987); Derynck et al., Nucl. Acids. Res., 15: 3188-3189 (1987); Derynck et al., Nucl. Acids. Res. 15: 3187 (1987); Seyedin et al., J. Biol. Chem., 261: 5693-5695 (1986); Madisen et al., DNA 7: 1-8 (1988); and Hanks et al., Proc. Natl. Acad. Sci. (U.S.A.), 85: 79-82 (1988).

TGF-β4 and TGF-β5 were cloned from a chicken chondrocyte cDNA library (Jakowlew et al., Molec. Endocrinol., 2: 1186-1195 (1988)) and from a frog oocyte cDNA library, respectively.

The pro region of TGF-β associates non-covalently with the mature TGF-β dimer (Wakefield et al., J. Biol. Chem., 263: 7646-7654 (1988); Wakefield et al., Growth Factors, 1: 203-218 (1989)), and the pro regions are found to be necessary for proper folding and secretion of the active mature dimers of both TGF-β and activin (Gray and Mason, Science, 247: 1328-1330 (1990)). The association between the mature and pro regions of TGF-β masks the biological activity of the mature dimer, resulting in formation of an inactive latent form. Latency is not a constant of the TGF-β superfamily, since the presence of the pro region has no effect on activin or inhibin biological activity.

A unifying feature of the biology of the proteins from the TGF-β superfamily is their ability to regulate developmental processes. TGF-β has been shown to have numerous regulatory actions on a wide variety of both normal and neoplastic cells. TGF-β is multifunctional, as it can either stimulate or inhibit cell proliferation, differentiation, and other critical processes in cell function (Sporn and Roberts, supra).

One member of the TGF-β superfamily, EBAF, is expressed in endometrium only in the late secretory phase and during abnormal endometrial bleeding. Kothapalli et al., J. Clin. Invest., 99: 2342-2350 (1997). Human endometrium is unique in that it is the only tissue in the body that bleeds at regular intervals. In addition, abnormal endometrial bleeding is one of the most common manifestations of gynecological diseases, and is a prime indication for hysterectomy. In situ hybridization showed that the mRNA of EBAF was expressed in the stroma without any significant mRNA expression in the endometrial glands or endothelial cells.

The predicted protein sequence of EBAF showed a strong homology to the protein encoded by mouse lefty/stra3 of the TGF-β superfamily. A motif search revealed that the predicted EBAF protein contains most of the cysteine residues which are conserved among the TGF-β-related proteins and which are necessary for the formation of the cysteine knot structure. The EBAF sequence contains an additional cysteine residue, 12 amino acids upstream from the first conserved cysteine residue. The only other family members known to contain an additional cysteine residue are TGF-βs, inhibins, and GDF-3. EBAF, similar to LEFTY, GDF-3/Vgr2, and GDF-9, lacks the cysteine residue that is known to form the intermolecular disulfide bond. Therefore, EBAF appears to be an additional member of the TGF-β superfamily with an unpaired cysteine residue that may not exist as a dimer. However, hydrophobic contacts between the two monomer subunits may promote dimer formation. Fluorescence in situ hybridization showed that the ebaf gene is located on human chromosome 1 at band q42.1.

Additional members of the TGF-β superfamily, such as those related to EBAF, are being searched for by industry and academics. We herein describe the identification and characterization of novel polypeptides having homology to EBAF, designated herein as PRO317 polypeptides.

18. PRO301

The widespread occurrence of cancer has prompted the devotion of considerable resources and discovering new treatments of treatment. One particular method involves the creation of tumor or cancer specific monoclonal antibodies (mAbs) which are specific to tumor antigens. Such mAbs, which can distinguish between normal and cancerous cells are useful in the diagnosis, prognosis and treatment of the disease. Particular antigens are known to be associated with neoplastic diseases, such as colorectal cancer.

One particular antigen, the A33 antigen is expressed in more than 90% of primary or metastatic colon cancers as well as normal colon epithelium. Since colon cancer is a widespread disease, early diagnosis and treatment is an important medical goal. Diagnosis and treatment of colon cancer can be implemented using monoclonal antibodies (mAbs) specific therefore having fluorescent, nuclear magnetic or radioactive tags. Radioactive gene, toxins and/or drug tagged mAbs can be used for treatment in situ with minimal patient description. mAbs can also be used to diagnose during the diagnosis and treatment of colon cancers. For example, when the serum levels of the A33 antigen are elevated in a patient, a drop of the levels after surgery would indicate the tumor resection was successful. On the other hand, a subsequent rise in serum A33 antigen levels after surgery would indicate that metastases of the original tumor may have formed or that new primary tumors may have appeared. Such monoclonal antibodies can be used in lieu of, or in conjunction with surgery and/or other chemotherapies. For example, U.S. Pat. No. 4,579,827 and U.S. Ser. No. 424,991 (E.P. 199,141) are directed to therapeutic administration of monoclonal antibodies, the latter of which relates to the application of anti-A33 mAb.

Many cancers of epithelial origin have adenovirus receptors. In fact, adenovirus-derived vectors have been proposed as a means of inserting antisense nucleic acids into tumors (U.S. Pat. No. 5,518,885). Thus, the association of viral receptors with neoplastic tumors is not unexpected.

We herein describe the identification and characterization of novel polypeptides having homology to certain cancer-associated antigens, designated herein as PRO301 polypeptides.

19. PRO224

Cholesterol uptake can have serious implications on one's health. Cholesterol uptake provides cells with most of the cholesterol they require for membrane synthesis. If this uptake is blocked, cholesterol accumulates in the blood and can contribute to the formation of atherosclerotic plaques in blood vessel walls. Most cholesterol is transported in the blood bound to protein in the form of complexes known as low-density lipoproteins (LDLs). LDLs are endocytosed into cells via LDL receptor proteins. Therefore, LDL receptor proteins, and proteins having homology thereto, are of interest to the scientific and medical communities.

Membrane-bound proteins and receptors can play an important role in the formation, differentiation and maintenance of multicellular organisms. The LDL receptors are an example of membrane-bound proteins which are involved in the synthesis and formation of cell membranes, wherein the health of an individual is affected directly and indirectly by its function. Many membrane-bound proteins act as receptors such as the LDL receptor. These receptors can function to endocytose substrates or they can function as a receptor for a channel. Other membrane-bound proteins function as signals or antigens.

Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule regulators of the relevant receptor/ligand interaction. In the case of the LDL receptor, it is desirable to find molecules which enhance endocytosis so as to lower blood cholesterol levels and plaque formation. It is also desirable to identify molecules which inhibit endocytosis so that these molecules can be avoided or regulated by individuals having high blood cholesterol. Polypeptides which are homologous to lipoprotein receptors but which do not function as lipoprotein receptors are also of interest in the determination of the function of the fragments which show homology.

The following studies report on previously known low density lipoprotein receptors and related proteins including apolipoproteins: Sawamura, et al., Nippon Chemiphar Co, Japan patent application J09098787; Novak, S., et al., J. Biol. Chem., 271:(20)11732-6 (1996); Blaas, D., J. Virol., 69(11)7244-7 (November 1995); Scott, J., J. Inherit. Metab. Dis. (UK), 9/Supp. 1 (3-16) (1986); Yamamoto, et al., Cell, 39:27-38 (1984); Rebece, et al., Neurobiol. Aging, 15:5117 (1994); Novak, S., et al., J. Biol. Chemistry, 271:11732-11736(1996); and Sestavel and Fruchart, Cell Mol. Biol., 40(4):461-81 (June 1994). These publications and others published prior to the filing of this application provide further background to peptides already known in the art.

Efforts are being undertaken by both industry and academia to identify new, native membrane-bound receptor proteins, particularly those having homology to lipoprotein receptors. We herein describe the identification and characterization of novel polypeptides having homology to lipoprotein receptors, designated herein as PRO224 polypeptides.

20. PRO222

Complement is a group of proteins found in the blood that are important in humoral immunity and inflammation. Complement proteins are sequentially activated by antigen-antibody complexes or by proteolytic enzymes. When activated, complement proteins kill bacteria and other microorganisms, affect vascular permeability, release histamine and attract white blood cells. Complement also enhances phagocytosis when bound to target cells. In order to prevent harm to autologous cells, the complement activation pathway is tightly regulated.

Deficiencies in the regulation of complement activation or in the complement proteins themselves may lead to immunecomplex diseases, such as systemic lupus erythematosus, and may result in increased susceptibility to bacterial infection. In all cases, early detection of complement deficiency is desirable so that the patient can begin treatment. Thus, research efforts are currently directed toward identification of soluble and membrane proteins that regulate complement activation.

Proteins known to be important in regulating complement activation in humans include Factor H and Complement receptor type 1 (CR1). Factor H is a 150 kD soluble serum protein that interacts with complement protein C3b to accelerate the decay of C3 convertase and acts as a cofactor for Factor I-mediated cleavage of complement protein C4b. Complement receptor type 1 is a 190-280 kD membrane bound protein found in mast cells and most blood cells. CR1 interacts with complement proteins C3b, C4b, and iC3b to accelerate dissociation of C3 convertases, acts as a cofactor for Factor I-mediated cleavage of C3b and C4b, and binds immune complexes and promotes their dissolution and phagocytosis.

Proteins which have homology to complement proteins are of particular interest to the medical and industrial communities. Often, proteins having homology to each other have similar function. It is also of interest when proteins having homology do not have similar functions, indicating that certain structural motifs identify information other than function, such as locality of function.

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound proteins, particularly those having homology to known proteins involved in the complement pathway. Proteins involved in the complement pathway were reviewed in Birmingham D J (1995), Critical Reviews in Immunology, 15(2): 133-154 and in Abbas A K, et al. (1994) Cellular and Molecular Immunology, 2nd Ed. W. B. Saunders Company, Philadelphia, pp 295-315.

We herein describe the identification and characterization of novel polypeptides having homology to complement receptors, designated herein as PRO222 polypeptides.

21. PRO234

The successful function of many systems within multicellular organisms is dependent on cell-cell interactions. Such interactions are affected by the alignment of particular ligands with particular receptors in a manner which allows for ligand-receptor binding and thus a cell-cell adhesion. While protein-protein interactions in cell recognition have been recognized for some time, only recently has the role of carbohydrates in physiologically relevant recognition been widely considered (see B. K. Brandley et al., J. Leuk. Biol. 40: 97 (1986) and N. Sharon et al., Science 246: 227 (1989). Oligosaccharides are well positioned to act as recognition novel lectins due to their cell surface location and structural diversity. Many oligosaccharide structures can be created through the differential activities of a smaller number of glycosyltransferases. The diverse structures of oligosaccharides can be generated by transcription of relatively few gene products, which suggests that the oligosaccharides are a plausible mechanism by which is directed a wide range of cell-cell interactions. Examples of differential expression of cell surface carbohydrates and putative carbohydrate binding proteins (lectins) on interacting cells have been described (J. Dodd & T. M. Jessel, J. Neurosci. 5: 3278 (1985); L. J. Regan et al., Proc. Natl. Acad. Sci. U.S.A. 83: 2248 (1986); M. Constantine-Paton et al., Nature 324: 459 (1986); and M. Tiemeyer et al., J. Biol. Chem. 263: 1671 (1989). One interesting member of the lectin family are selectins.

The migration of leukocytes to sites of acute or chronic inflammation involves adhesive interactions between these cells and the endothelium. This specific adhesion is the initial event in the cascade that is initiated by inflammatory insults, and it is, therefore, of paramount importance to the regulated defense of the organism.

The types of cell adhesion molecules that are involved in the interaction between leukocytes and the endothelium during an inflammatory response currently stands at four: (1) selectins; (2) (carbohydrate and glycoprotein) ligands for selectins; (3) integrins; and (4) integrin ligands, which are members of the immunoglobulin gene superfamily.

The selectins are cell adhesion molecules that are unified both structurally and functionally. Structurally, selectins are characterized by the inclusion of a domain with homology to a calcium-dependent lectin (C-lectins), an epidermal growth factor (egf)-like domain and several complement binding-like domains, Bevilacqua, M. P. et al., Science 243: 1160-1165 (1989); Johnston et al, Cell 56: 1033-1044 (1989); Lasky et al, Cell 56: 1045-1055 (1989); Siegalman, M. et al., Science 243: 1165-1172 (1989); Stoolman, L. M., Cell 56: 907-910 (1989). Functionally, selectins share the common property of their ability to mediate cell binding through interactions between their lectin domains and cell surface carbohydrate ligands (Brandley, B, et al., Cell 63, 861-863 (1990); Springer, T. and Lasky, L. A., Nature 349, 19-197 (1991); Bevilacqua, M. P. and Nelson, R. M., J. Clin. Invest. 91 379-387 (1993) and Tedder et al., J. Exp. Med. 170: 123-133 (1989).

There are three members identified so far in the selectin family of cell adhesion molecules: L-selectin (also called peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1, gp90^(MEL), gp100^(MEL), gp110^(MEL), MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, DREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1) and P-selectin (LEC-CAM-3, LECAM-3, GMP-140, PADGEM).

The identification of the C-lectin domain has led to an intense effort to define carbohydrate binding ligands for proteins containing such domains. E-selectin is believed to recognize the carbohydrate sequence NeuNAcα2-3Galβ1-4(Fucα1-3)GlcNAc (sialyl-Lewis x, or sLe^(x)) and related oligosaccharides, Berg et al., J. Biol. Chem. 265: 14869-14872(1991); Lowe et al., Cell 63: 475-484(1990); Phillips et al., Science 250: 1130-1132 (1990); Tiemeyer et al., Proc. Natl. Acad. Sci. U.S.A. 88: 1138-1142 (1991).

L-selectin, which comprises a lectin domain, performs its adhesive function by recognizing carbohydrate-containing ligands on endothelial cells. L-selectin is expressed on the surface of leukocytes, such as lymphocytes, neutrophils, monocytes and eosinophils, and is involved with the trafficking of lymphocytes to peripheral lymphoid tissues (Gallatin et al., Nature 303: 30-34 (1983)) and with acute neutrophil-medicated inflammatory responses (Watson, S. R., Nature 349: 164-167 (1991)). The amino acid sequence of L-selectin and the encoding nucleic acid sequence are, for example, disclosed in U.S. Pat. No. 5,098,833 issued Mar. 24, 1992.

L-selectin (LECAM-1) is particularly interesting because of its ability to block neutrophil influx (Watson et al., Nature 349: 164-167 (1991). It is expressed in chronic lymphocytic leukemia cells which bind to HEV (Spertini et al., Nature 349: 691-694 (1991). It is also believed that HEV structures at sites of chronic inflammation are associated with the symptoms of diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis.

E-selectin (ELAM-1), is particularly interesting because of its transient expression on endothelial cells in response to IL-1 or TNF. Bevilacqua et al., Science 243: 1160 (1989). The time course of this induced expression (2-8 h) suggests a role for this receptor in initial neutrophil induced extravasation in response to infection and injury. It has further been reported that anti-ELAM-1 antibody blocks the influx of neutrophils in a primate asthma model and thus is beneficial for preventing airway obstruction resulting from the inflammatory response. Gundel et al., J. Clin. Invest. 88: 1407 (1991).

The adhesion of circulating neutrophils to stimulated vascular endothelium is a primary event of the inflammatory response. P-selectin has been reported to recognize the Lewis x structure (Galβ1-4(Fucα1-3) GlcNAc), Larsen et al., Cell 63: 467-474(1990). Others report that an additional terminal linked sialic acid is required for high affinity binding, Moore et al., J. Cell. Biol. 112: 491-499 (1991). P-selectin has been shown to be significant in acute lung injury. Anti-P-selectin antibody has been shown to have strong protective effects in a rodent lung injury model. M. S. Mulligan et al., J. Clin. Invest. 90: 1600 (1991).

We herein describe the identification and characterization of novel polypeptides having homology to lectin proteins, herein designated as PRO234 polypeptides.

22. PRO231

Some of the most important proteins involved in the above described regulation and modulation of cellular processes are the enzymes which regulate levels of protein phosphorylation in the cell. For example, it is known that the transduction of signals that regulate cell growth and differentiation is regulated at least in part by phosphorylation and dephosphorylation of various cellular proteins. The enzymes that catalyze these processes include the protein kinases, which function to phosphorylate various cellular proteins, and the protein phosphatases, which function to remove phosphate residues from various cellular proteins. The balance of the level of protein phosphorylation in the cell is thus mediated by the relative activities of these two types of enzymes.

Protein phosphatases represent a growing family of enzymes that are found in many diverse forms, including both membrane-bound and soluble forms. While many protein phosphatases have been described, the functions of only a very few are beginning to be understood (Tonks, Semin. Cell Biol. 4:373-453 (1993) and Dixon, Recent Prog. Horm. Res. 51:405-414 (1996)). However, in general, it appears that many of the protein phosphatases function to modulate the positive or negative signals induced by various protein kinases. Therefore, it is likely that protein phosphatases play critical roles in numerous and diverse cellular processes.

Given the physiological importance of the protein phosphatases, efforts are being undertaken by both industry and academia to identify new, native phosphatase proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel phosphatase proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to acid phosphatases, designated herein as PRO231 polypeptides.

23. PRO229

Scavenger receptors are known to protect IgG molecules from catabolic degradation. Riechmann and Hollinger, Nature Biotechnology, 15:617 (1997). In particular, studies of the CH2 and CH3 domains have shown that specific sequences of these domains are important in determining the half-lives of antibodies. Ellerson, et al., J. Immunol., 116: 510 (1976); Yasmeen, et al., J. Immunol. 116: 518 (1976; Pollock, et al., Eur. J. Immunol., 20: 2021 (1990). Scavenger receptor proteins and antibodies thereto are further reported in U.S. Pat. No. 5,510,466 to Krieger, et al. Due to the ability of scavenger receptors to increase the half-life of polypeptides and their involvement in immune function, molecules having homology to scavenger receptors are of importance to the scientific and medical community.

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly those having homology to scavenger receptors. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to scavenger receptors, designated herein as PRO229 polypeptides.

24. PRO238

Oxygen free radicals and antioxidants appear to play an important role in the central nervous system after cerebral ischemia and reperfusion. Moreover, cardiac injury, related to ischaemia and reperfusion has been reported to be caused by the action of free radicals. Additionally, studies have reported that the redox state of the cell is a pivotal determinant of the fate of the cells. Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. Thus, the control of oxidation and reduction is important for a number of reasons including for control and prevention of strokes, heart attacks, oxidative stress and hypertension. In this regard, reductases, and particularly, oxidoreductases, are of interest. Publications further describing this subject matter include Kelsey, et al., Br. J. Cancer, 76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997).

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly secreted proteins which have homology to reductase. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to reductase, designated herein as PRO238 polypeptides.

25. PRO233

Studies have reported that the redox state of the cell is an important determinant of the fate of the cell. Furthermore, reactive oxygen species have been reported to be cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. Thus, the control of oxidation and reduction is important for a number of reasons, including the control and prevention of strokes, heart attacks, oxidative stress and hypertension. Oxygen free radicals and antioxidants appear to play an important role in the central nervous system after cerebral ischemia and reperfusion. Moreover, cardiac injury, related to ischaemia and reperfusion has been reported to be caused by the action of free radicals. In this regard, reductases, and particularly, oxidoreductases, are of interest. In addition, the transcription factors, NF-kappa B and AP-1, are known to be regulated by redox state and to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications. Publications further describing this subject matter include Kelsey, et al., Br. J. Cancer, 76(7):852-4 (1997); Friedrich and Weiss, J. Theor. Biol., 187(4):529-40 (1997) and Pieulle, et al., J. Bacteriol., 179(18):5684-92 (1997). Given the physiological importance of redox reactions in vivo, efforts are currently being under taken to identify new, native proteins which are involved in redox reactions. We describe herein the identification of novel polypeptides which have homology to reductase, designated herein as PRO233 polypeptides.

26. PRO223

The carboxypeptidase family of exopeptidases constitutes a diverse group of enzymes that hydrolyze carboxyl-terminal amide bonds in polypeptides, wherein a large number of mammalian tissues produce these enzymes. Many of the carboxypeptidase enzymes that have been identified to date exhibit rather strong cleavage specificities for certain amino acids in polypeptides. For example, carboxypeptidase enzymes have been identified which prefer lysine, arginine, serine or amino acids with either aromatic or branched aliphatic side chains as substrates at the carboxyl terminus of the polypeptide.

With regard to the serine carboxypeptidases, such amino acid specific enzymes have been identified from a variety of different mammalian and non-mammalian organisms. The mammalian serine carboxypeptidase enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.

In light of the physiological importance of the serine carboxypeptidases, efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins and specifically novel carboxypeptidases. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. We describe herein novel polypeptides having homology to one or more serine carboxypeptidase polypeptides, designated herein as PRO223 polypeptides.

27. PRO235

Plexin was first identified in Xenopus tadpole nervous system as a membrane glycoprotein which was shown to mediate cell adhesion via a homophilic binding mechanism in the presence of calcium ions. Strong evolutionary conservation between Xenopus, mouse and human homologs of plexin has been observed. [Kaneyama et al., Biochem. And Biophys. Res. Comm. 226: 524-529 (1996)]. Given the physiological importance of cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in cell adhesion. We describe herein the identification of a novel polypeptide which has homology to plexin, designated herein as PRO235.

28. PRO236 and PRO262

β-galactosidase is a well known enzymatic protein which functions to hydrolyze β-galactoside molecules. β-galactosidase has been employed for a variety of different applications, both in vitro and in vivo and has proven to be an extremely useful research tool. As such, there is an interest in obtaining novel polypeptides which exhibit homology to the β-galactosidase polypeptide.

Given the strong interest in obtaining novel polypeptides having homology to β-galactosidase, efforts are currently being undertaken by both industry and academia to identify new, native β-galactosidase homolog proteins. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel β-galactosidase-like proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. We herein describe novel polypeptides having significant homology to the β-galactosidase enzyme, designated herein as PRO236 and PRO262 polypeptides.

29. PRO239

Densin is a glycoprotein which has been isolated from the brain which has all the hallmarks of an adhesion molecule. It is highly concentrated at synaptic sites in the brain and is expressed prominently in dendritic processes in developing neurons. Densin has been characterized as a member of the O-linked sialoglycoproteins. Densin has relevance to medically important processes such as regeneration. Given the physiological importance of synaptic processes and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. We describe herein the identification of novel polypeptides which have homology to densin, designated herein as PRO239 polypeptides.

30. PRO257

Ebnerin is a cell surface protein associated with von Ebner glands in mammals. Efforts are being undertaken by both industry and academia to identify new, native cell surface receptor proteins and specifically those which possess sequence homology to cell surface proteins such as ebnerin. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor proteins. We herein describe the identification of novel polypeptides having significant homology to the von Ebner's gland-associated protein ebnerin, designated herein as PRO257 polypeptides.

31. PRO260

Fucosidases are enzymes that remove fucose residues from fucose containing proteoglycans. In some pathological conditions, such as cancer, rheumatoid arthritis, and diabetes, there is an abnormal fucosylation of serum proteins. Therefore, fucosidases, and proteins having homology to fucosidase, are of importance to the study and abrogation of these conditions. In particular, proteins having homology to the alpha-1-fucosidase precursor are of interest. Fucosidases and fucosidase inhibitors are further described in U.S. Pat. Nos. 5,637,490, 5,382,709, 5,240,707, 5,153,325, 5,100,797, 5,096,909 and 5,017,704. Studies are also reported in Valk, et al., J. Virol., 71(9):6796 (1997), Aktogu, et al., Monaldi. Arch. Chest Dis. (Italy), 52(2): 118(1997) and Focarelli, et al., Biochem. Biophys. Res. Commun. (U.S.), 234(1):54 (1997).

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins. Of particular interest are proteins having homology to the alpha-1-fucosidase precursor. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to fucosidases, designated herein as PRO260 polypeptides.

32. PRO263

CD44 is a cell surface adhesion molecule involved in cell-cell and cell-matrix interactions. Hyaluronic acid, a component of the extracellular matrix is a major ligand. Other ligands include collagen, fibronectin, laminin, chrondroitin sulfate, mucosal addressin, serglycin and osteoponin. CD44 is also important in regulating cell traffic, lymph node homing, transmission of growth signals, and presentation of chemokines and growth factors to traveling cells. CD44 surface proteins are associated with metastatic tumors and CD44 has been used as a marker for HIV infection. Certain splice variants are associated with metastasis and poor prognosis of cancer patients. Therefore, molecules having homology with CD44 are of particular interest, as their homology indicates that they may have functions related to those functions of CD44. CD44 is further described in U.S. Pat. Nos. 5,506,119, 5,504,194 and 5,108,904; Gerberick, et al., Toxicol. Appl. Pharmacol., 146(1):1 (1997); Wittig, et al., Immunol. Letters (Netherlands), 57(1-3):217 (1997); and Oliveira and Odell, Oral Oncol. (England), 33(4):260 (1997).

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly transmembrane proteins with homology to CD44 antigen. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to CD44 antigen, designated herein as PRO263 polypeptides.

33. PRO270

Thioredoxins effect reduction-oxidation (redox) state. Many diseases are potentially related to redox state and reactive oxygen species may play a role in many important biological processes. The transcription factors, NF-kappa B and AP-1, are regulated by redox state and are known to affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis and diabetic complications. Such proteins may also play a role in cellular antioxidant defense, and in pathological conditions involving oxidative stress such as stroke and inflammation in addition to having a role in apoptosis. Therefore, thioredoxins, and proteins having homology thereto, are of interest to the scientific and medical communities.

We herein describe the identification and characterization of novel polypeptides having homology to thioredoxin, designated herein as PRO270 polypeptides.

34. PRO271

The proteoglycan link protein is a protein which is intimately associated with various extracellular matrix proteins and more specifically with proteins such as collagen. For example, one primary component of collagen is a large proteoglycan called aggrecan. This molecule is retained by binding to the glycosaminoglycan hyaluronan through the amino terminal G1 globular domain of the core protein. This binding is stabilized by the proteoglycan link protein which is a protein that is also associated with other tissues containing hyaluronan binding proteoglycans such as versican.

Link protein has been identified as a potential target for autoimmune antibodies in individuals who suffer from juvenile rheumatoid arthritis (see Guerassimov et al., J. Rheumatology 24(5):959-964 (1997)). As such, there is strong interest in identifying novel proteins having homology to link protein. We herein describe the identification and characterization of novel polypeptides having such homology, designated herein as PRO271 polypeptides.

35. PRO272

Reticulocalbin is an endoplasmic reticular protein which may be involved in protein transport and luminal protein processing. Reticulocalbin resides in the lumen of the endopladsmic rerticulum, is known to bind calcium, and may be involved in a luminal retention mechanism of the endoplasmic reticulum. It contains six domains of the EF-hand motif associated with high affinity calcium binding. We describe herein the identification and characterization of a novel polypeptide which has homology to the reticulocalbin protein, designated herein as PRO272.

36. PRO294

Collagen, a naturally occurring protein, finds wide application in industry. Chemically hydrolyzed natural collagen can be denatured and renatured by heating and cooling to produce gelatin, which is used in photographic and medical, among other applications. Collagen has important properties such as the ability to form interchain aggregates having a conformation designated as a triple helix. We herein describe the identification and characterization of a novel polypeptide which has homology to portions of the collagen molecule, designated herein as PRO294.

37. PRO295

The integrins comprise a supergene family of cell-surface glycoprotein receptors that promote cellular adhesion. Each cell has numerous receptors that define its cell adhesive capabilities. Integrins are involved in a wide variety of interaction between cells and other cells or matrix components. The integrins are of particular importance in regulating movement and function of immune system cells The platelet IIb/IIIA integrin complex is of particular importance in regulating platelet aggregation. A member of the integrin family, integrin β-6, is expressed on epithelial cells and modulates epithelial inflammation. Another integrin, leucocyte-associated antigen-1 (LFA-1) is important in the adhesion of lymphocytes during an immune response. The integrins are expressed as heterodimers of non-covalently associated alpha and beta subunits. Given the physiological importance of cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in cell adhesion. We describe herein the identification and characterization of a novel polypeptide which has homology to integrin, designated herein as PRO295.

38. PRO293

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats. Another protein of particular interest which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Other studies reporting on the biological functions of proteins having leucine-rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation (decorin binding to transforming growth factors involvement for treatment for cancer, wound healing and scarring).

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and homology to known neuronal leucine rich repeat proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound proteins having leucine rich repeats. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of a novel polypeptide which has homology to leucine rich repeat proteins, designated herein as PRO293.

39. PRO247

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome and Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1):111-116 (July 1995), reporting that platelets have leucine rich repeats. Another protein of particular interest which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Other studies reporting on the biological functions of proteins having leucine-rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement); and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation (decorin binding to transforming growth factors involvement for treatment for cancer, wound healing and scarring).

Densin is a glycoprotein which has been isolated from the brain which has all the hallmarks of an adhesion molecule. It is highly concentrated at synaptic sites in the brain and is expressed prominently in dendritic processes in developing neurons. Densin has been characterized as a member of the O-linked sialoglycoproteins. Densin has relevance to medically important processes such as regeneration. Given the physiological importance of synaptic processes and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. Densin is further described in Kennedy, M. B, Trends Neurosci. (England), 20(6):264 (1997) and Apperson, et al., J. Neurosci., 16(21):6839 (1996).

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and homology to known proteins having leucine rich repeats such as KIAA0231 and densin. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound proteins having leucine rich repeats. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of a novel polypeptide which has homology to leucine rich repeat proteins, designated herein as PRO247.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Proteases are enzymatic proteins which are involved in a large number of very important biological processes in mammalian and non-mammalian organisms. Numerous different protease enzymes from a variety of different mammalian and non-mammalian organisms have been both identified and characterized. The mammalian protease enzymes play important roles in many different biological processes including, for example, protein digestion, activation, inactivation, or modulation of peptide hormone activity, and alteration of the physical properties of proteins and enzymes.

In light of the important physiological roles played by protease enzymes, efforts are currently being undertaken by both industry and academia to identify new, native protease homologs. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. We herein describe the identification of novel polypeptides having homology to various protease enzymes, designated herein as PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides.

41. PRO328

The GLIP protein family has been characterized as comprising zinc-finger proteins which play important roles in embryogenesis. These proteins may function as transcriptional regulatory proteins and are known to be amplified in a subset of human tumors. Glioma pathogenesis protein is structurally related to a group of plant pathogenesis-related proteins. It is highly expressed in glioblastoma. See U.S. Pat. Nos. 5,582,981 (issued Dec. 10, 1996) and 5,322,801 (issued June 21, 1996), Ellington, A. D. et al., Nature 346:818 (1990), Grindley, J. C. et al., Dev. Biol., 188(2):337 (1997), Marine, J. C. et al., Mech. Dev., 63(2):211 (1997), The CRISP or cysteine rich secretory protein family are a group of proteins which are also structurally related to a group of plant pathogenesis proteins. [Schwidetzky, U., Biochem. J., 321:325 (1997), Pfisterer, P., Mol. Cell Biol., 16(11):6160 (1996), Kratzschmar, J., Eur. J. Biochem., 236(3):827 (1996)]. We describe herein the identification of a novel polypeptide which has homology to GLIP and CRISP, designated herein as PRO328 polypeptides.

42. PRO335, PRO331 and PRO326

Protein-protein interactions include receptor and antigen complexes and signaling mechanisms. As more is known about the structural and functional mechanisms underlying protein-protein interactions, protein-protein interactions can be more easily manipulated to regulate the particular result of the protein-protein interaction. Thus, the underlying mechanisms of protein-protein interactions are of interest to the scientific and medical community.

All proteins containing leucine-rich repeats are thought to be involved in protein-protein interactions. Leucine-rich repeats are short sequence motifs present in a number of proteins with diverse functions and cellular locations. The crystal structure of ribonuclease inhibitor protein has revealed that leucine-rich repeats correspond to beta-alpha structural units. These units are arranged so that they form a parallel beta-sheet with one surface exposed to solvent, so that the protein acquires an unusual, nonglubular shape. These two features have been indicated as responsible for the protein-binding functions of proteins containing leucine-rich repeats. See, Kobe and Deisenhofer, Trends Biochem. Sci., 19(10):415-421 (October 1994).

A study has been reported on leucine-rich proteoglycans which serve as tissue organizers, orienting and ordering collagen fibrils during ontogeny and are involved in pathological processes such as wound healing, tissue repair, and tumor stroma formation. Iozzo, R. V., Crit. Rev. Biochem. Mol. Biol., 32(2):141-174 (1997). Others studies implicating leucine rich proteins in wound healing and tissue repair are De La Salle, C., et al., Vouv. Rev. Fr. Hematol. (Germany), 37(4):215-222 (1995), reporting mutations in the leucine rich motif in a complex associated with the bleeding disorder Bernard-Soulier syndrome, Chlemetson, K. J., Thromb. Haemost. (Germany), 74(1): 111-116 (July 1995), reporting that platelets have leucine rich repeats and Ruoslahti, E. I., et al., WO9110727-A by La Jolla Cancer Research Foundation reporting that decorin binding to transforming growth factorβ has involvement in a treatment for cancer, wound healing and scarring. Related by function to this group of proteins is the insulin like growth factor (IGF), in that it is useful in wound-healing and associated therapies concerned with re-growth of tissue, such as connective tissue, skin and bone; in promoting body growth in humans and animals; and in stimulating other growth-related processes. The acid labile subunit of IGF (ALS) is also of interest in that it increases the half-life of IGF and is part of the IGF complex in vivo.

Another protein which has been reported to have leucine-rich repeats is the SLIT protein which has been reported to be useful in treating neuro-degenerative diseases such as Alzheimer's disease, nerve damage such as in Parkinson's disease, and for diagnosis of cancer, see, Artavanistsakonas, S. and Rothberg, J. M., WO9210518-A1 by Yale University. Of particular interest is LIG-1, a membrane glycoprotein that is expressed specifically in glial cells in the mouse brain, and has leucine rich repeats and immunoglobulin-like domains. Suzuki, et al., J. Biol. Chem. (U.S.), 271(37):22522 (1996). Other studies reporting on the biological functions of proteins having leucine rich repeats include: Tayar, N., et al., Mol. Cell Endocrinol., (Ireland), 125(1-2):65-70 (December 1996) (gonadotropin receptor involvement); Miura, Y., et al., Nippon Rinsho (Japan), 54(7):1784-1789 (July 1996) (apoptosis involvement); Harris, P. C., et al., J. Am. Soc. Nephrol., 6(4):1125-1133 (October 1995) (kidney disease involvement).

Efforts are therefore being undertaken by both industry and academia to identify new proteins having leucine rich repeats to better understand protein-protein interactions. Of particular interest are those proteins having leucine rich repeats and homology to known proteins having leucine rich repeats such as LIG-1, ALS and decorin. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound proteins having leucine rich repeats. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We describe herein the identification and characterization of novel polypeptides which have homology to proteins of the leucine rich repeat superfamily, designated herein as PRO335, PRO331 and PRO326 polypeptides.

43. PRO332

Secreted proteins comprising a repeat characterized by an arrangement of conserved leucine residues (leucine-rich repeat motif) have diverse biological roles. Certain proteoglycans, such as biglycan, fibromodulin and decorin, are, for example, characterized by the presence of a leucine-rich repeat of about 24 amino acids [Ruoslahti, Ann. Rev. Cell. Biol. 4 229-255 (1988); Oldberg et al., EMBO J. 8, 2601-2604 (1989)]. In general, proteoglycans are believed to play a role in regulating extracellular matrix, cartilage or bone function. The proteoglycan decorin binds to collagen type I and II and affects the rate of fibril formation. Fibromodulin also binds collagen and delays fibril formation. Both fibromodulin and decorin inhibit the activity of transforming growth factor beta (TGF-β) (U.S. Pat. No. 5,583,103 issued Dec. 10, 1996). TGF-β is known to play a key role in the induction of extracellular matrix and has been implicated in the development of fibrotic diseases, such as cancer and glomerulonephritis. Accordingly, proteoglycans have been proposed for the treatment of fibrotic cancer, based upon their ability to inhibit TGF-β's growth stimulating activity on the cancer cell. Proteoglycans have also been described as potentially useful in the treatment of other proliferative pathologies, including rheumatoid arthritis, arteriosclerosis, adult respiratory distress syndrome, cirrhosis of the liver, fibrosis of the lungs, post-myocardial infarction, cardiac fibrosis, post-angioplasty restenosis, renal interstitial fibrosis and certain dermal fibrotic conditions, such as keloids and scarring, which might result from burn injuries, other invasive skin injuries, or cosmetic or reconstructive surgery (U.S. Pat. No. 5,654,270, issued Aug. 5, 1997).

We describe herein the identification and characterization of novel polypeptides which have homology to proteins of the leucine rich repeat superfamily, designated herein as PRO332 polypeptides.

44. PRO334

Microfibril bundles and proteins found in association with these bundles, particularly attachment molecules, are of interest in the field of dermatology, particularly in the study of skin which has been damaged from aging, injuries or the sun. Fibrillin microfibrils define the continuous elastic network of skin, and are present in dermis as microfibril bundles devoid of measurable elastin extending from the dermal-epithelial junction and as components of the thick elastic fibers present in the deep reticular dermis. Moreover, Marfan syndrome has been linked to mutations which interfere with multimerization of fibrillin monomers or other connective tissue elements.

Fibulin-1 is a modular glycoprotein with amino-terminal anaphlatoxin-like modules followed by nine epidermal growth factor (EGF)-like modules and, depending on alternative splicing, four possible carboxyl termini. Fibulin-2 is a novel extracellular matrix protein frequently found in close association with microfibrils containing either fibronectin or fibrillin. Thus, fibrillin, fibulin, and molecules related thereto are of interest, particularly for the use of preventing skin from being damaged from aging, injuries or the sun, or for restoring skin damaged from same. Moreover, these molecules are generally of interest in the study of connective tissue and attachment molecules and related mechanisms. Fibrillin, fibulin and related molecules are further described in Adams, et al., J. Mol. Biol., 272(2):22636 (1997); Kielty and Shuttleworth, Microsc. Res. Tech., 38(4):413-27.(1997); and Child, J. Card. Surg. 12(2Supp.):131-5 (1997).

Currently, efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins, particularly secreted proteins which have homology to fibulin and fibrillin. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

We herein describe the identification and characterization of novel polypeptides having homology to fibulin and fibrillin, designated herein as PRO334 polypeptides.

45. PRO346

The widespread occurrence of cancer has prompted the devotion of considerable resources and discovering new treatments of treatment. One particular method involves the creation of tumor or cancer specific monoclonal antibodies (mAbs) which are specific to tumor antigens. Such mAbs, which can distinguish between normal and cancerous cells are useful in the diagnosis, prognosis and treatment of the disease. Particular antigens are known to be associated with neoplastic diseases, such as colorectal and breast cancer. Since colon cancer is a widespread disease, early diagnosis and treatment is an important medical goal. Diagnosis and treatment of cancer can be implemented using monoclonal antibodies (mAbs) specific therefore having fluorescent, nuclear magnetic or radioactive tags. Radioactive genes, toxins and/or drug tagged mAbs can be used for treatment in situ with minimal patient description.

Carcinoembryonic antigen (CEA) is a glycoprotein found in human colon cancer and the digestive organs of a 2-6 month human embryos. CEA is a known human tumor marker and is widely used in the diagnosis of neoplastic diseases, such as colon cancer. For example, when the serum levels of CEA are elevated in a patient, a drop of CEA levels after surgery would indicate the tumor resection was successful. On the other hand, a subsequent rise in serum CEA levels after surgery would indicate that metastases of the original tumor may have formed or that new primary tumors may have appeared. CEA may also be a target for mAb, antisense nucleotides

46. PRO268

Protein disulfide isomerase is an enzymatic protein which is involved in the promotion of correct refolding of proteins through the establishment of correct disulfide bond formation. Protein disulfide isomerase was initially identified based upon its ability to catalyze the renaturation of reduced denatured RNAse (Goldberger et al., J. Biol. Chem. 239:1406-1410(1964) and Epstein et al., Cold Spring Harbor Symp. Quant. Biol. 28:439-449 (1963)). Protein disulfide isomerase has been shown to be a resident enzyme of the endoplasmic reticulum which is retained in the endoplasmic reticulum via a -KDEL or -HDEL amino acid sequence at its C-terminus.

Given the importance of disulfide bond-forming enzymes and their potential uses in a number of different applications, for example in increasing the yield of correct refolding of recombinantly produced proteins, efforts are currently being undertaken by both industry and academia to identify new, native proteins having homology to protein disulfide isomerase. Many of these efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel protein disulfide isomerase homologs. We herein describe a novel polypeptide having homology to protein disulfide isomerase, designated herein as PRO268.

47. PRO330

Prolyl 4-hydroxylase is an enzyme which functions to post-translationally hydroxylate proline residues at the Y position of the amino acid sequence Gly-X-Y, which is a repeating three amino acid sequence found in both collagen and procollagen. Hydroxylation of proline residues at the Y position of the Gly-X-Y amino acid triplet to form 4-hydroxyproline residues at those positions is required before newly synthesized collagen polypeptide chains may fold into their proper three-dimensional triple-helical conformation. If hydroxylation does not occur, synthesized collagen polypeptides remain non-helical, are poorly secreted by cells and cannot assemble into stable functional collagen fibrils. Vuorio et al., Proc. Natl. Acad. Sci. U.S.A. 89:7467-7470 (1992). Prolyl 4hydroxylase is comprised of at least two different polypeptide subunits, alpha and beta.

Efforts are being undertaken by both industry and academia to identify new, native secreted and membrane-bound receptor proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted and membrane-bound receptor proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci., 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)]. Based upon these efforts, Applicants have herein identified and describe a novel polypeptide having homology to the alpha subunit of prolyl 4-hydroxylase, designated herein as PRO330.

48. PRO339 and PRO310

Fringe is a protein which specifically blocks serrate-mediated activation of notch in the dorsal compartment of the Drosophila wing imaginal disc. Fleming, et al., Development, 124(15):2973-81 (1997). Therefore, fringe is of interest for both its role in development as well as its ability to regulate serrate, particularly serrate's signaling abilities. Also of interest are novel polypeptides which may have a role in development and/or the regulation of serrate-like molecules. Of particular interest are novel polypeptides having homology to fringe as identified and described herein, designated herein as PRO339 and PRO310 polypeptides.

49. PRO244

Lectins are a class of proteins comprising a region that binds carbohydrates specifically and non-covalently. Numerous lectins have been identified in higher animals, both membrane-bound and soluble, and have been implicated in a variety of cell-recognition phenomena and tumor metastasis.

Most lectins can be classified as either C-type (calcium-dependent) or S-type (thiol-dependent).

Lectins are thought to play a role in regulating cellular events that are initiated at the level of the plasma membrane. For example, plasma membrane associated molecules are involved in the activation of various subsets of lymphoid cells, e.g. T-lymphocytes, and it is known that cell surface molecules are responsible for activation of these cells and consequently their response during an immune reaction.

A particular group of cell adhesion molecules, selecting, belong in the superfamily of C-type lectins. This group includes L-selectin (peripheral lymph node homing receptor (pnHR), LEC-CAM-1, LAM-1, gp90^(MEL), gp100^(MEL), gp110^(MEL), MEL-14 antigen, Leu-8 antigen, TQ-1 antigen, DREG antigen), E-selectin (LEC-CAM-2, LECAM-2, ELAM-1), and P-selectin (LEC-CAM-3, LECAM-3, GMP-140, PADGEM). The structure of selectins consists of a C-type lectin (carbohydrate binding) domain, an epidermal growth factor-like (EGF-like) motif, and variable numbers of complement regulatory (CR) motifs. Selectins are associated with leukocyte adhesion, e.g. The attachment of neutrophils to venular endothelial cells adjacent to inflammation (E-selectin), or with the trafficking of lymphocytes from blood to secondary lymphoid organs, e.g. lymph nodes and Peyer's patches (L-selectin).

Another exemplary lectin is the cell-associated macrophage antigen, Mac-2 that is believed to be involved in cell adhesion and immune responses. Macrophages also express a lectin that recognizes Tn Ag, a human carcinoma-associated epitope.

Another C-type lectin is CD95 (Fas antigen/APO-1) that is an important mediator of immunologically relevant regulated or programmed cell death (apoptosis). “Apoptosis” is a non-necrotic cell death that takes place in metazoan animal cells following activation of an intrinsic cell suicide program. The cloning of Fas antigen is described in PCT publication WO 91/10448, and European patent application EP510691. The mature Fas molecule consists of 319 amino acids of which 157 are extracellular, 17 constitute the transmembrane domain, and 145 are intracellular. Increased levels of Fas expression at T cell surface have been associated with tumor cells and HIV-infected cells. Ligation of CD95 triggers apoptosis in the presence of interleukin-1 (IL-2).

C-type lectins also include receptors for oxidized low-density lipoprotein (LDL). This suggests a possible role in the pathogenesis of atherosclerosis.

We herein describe the identification and characterization of novel polypeptides having homology to C-type lectins, designated herein as PRO244 polypeptides.

SUMMARY OF THE INVENTION

1. PRO211 and PRO217

Applicants have identified cDNA clones that encode novel polypeptides having homology to EGF, designated in the present application as “PRO211 ” and “PRO217” polypeptides.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO211 or PRO217 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding EGF-like homologue PRO211 and PRO217 polypeptides of FIG. 2 (SEQ ID NO:2) and/or 4 (SEQ ID NO:4) indicated in FIG. 1 (SEQ ID NO1) and/or FIG. 3 (SEQ ID NO:3), respectively, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO211 and PRO217 EGF-like homologue PRO211 and PRO217 polypeptides. In particular, the invention provides isolated native sequence PRO211 and PRO217 EGF-like homologue polypeptides, which in one embodiment, includes an amino acid sequence comprising residues: 1 to 353 of FIG. 2 (SEQ ID NO:2) or (2) 1 to 379 of FIG. 4 (SEQ ID NO:4).

2. PRO230

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO230”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO230 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO230 polypeptide having amino acid residues 1 through 467 of FIG. 6 (SEQ ID NO:12), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO230 polypeptide. In particular, the invention provides isolated native sequence PRO230 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 467 of FIG. 6 (SEQ ID NO:12).

In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:13 (FIG. 7) which is herein designated as DNA20088.

3. PRO232

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO232”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO232 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO232 polypeptide having amino acid residues 1 to 114 of FIG. 9 (SEQ ID NO:18), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO232 polypeptide. In particular, the invention provides isolated native sequence PRO232 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 114 of FIG. 9 (SEQ ID NO:18).

4. PRO187

Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as “PRO187”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO187 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO187 polypeptide of FIG. 11 (SEQ ID NO:23), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid comprising the coding sequence of FIG. 10 (SEQ ID NO:22) or its complement. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA27864-1155, deposited with the ATCC under accession number ATCC 209375, alternatively the coding sequence of clone DNA27864-1155, deposited under accession number ATCC 209375.

In yet another embodiment, the invention provides isolated PRO187 polypeptide. In particular, the invention provides isolated native sequence PRO187 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 205 of FIG. 11 (SEQ ID NO:23). Alternatively, the invention provides a polypeptide encoded by the nucleic acid deposited under accession number ATCC 209375.

5. PRO265

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO265”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO265 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO265 polypeptide having amino acid residues 1 to 660 of FIG. 13 (SEQ ID NO:28), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO265 polypeptide. In particular, the invention provides isolated native sequence PRO265 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 660 of FIG. 13 (SEQ ID NO:28). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO265 polypeptide.

6. PRO219

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO219”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO219 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO219 polypeptide having amino acid residues 1 to 915 of FIG. 15 (SEQ ID NO:34), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO219 polypeptide. In particular, the invention provides isolated native sequence PRO219 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 915 of FIG. 15 (SEQ ID NO:34).

7. PRO246

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO246”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO246 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO246 polypeptide having amino acid residues 1 to 390 of FIG. 17 (SEQ ID NO:39), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO246 polypeptide. In particular, the invention provides isolated native sequence PRO246 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 390 of FIG. 17 (SEQ ID NO:39). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO246 polypeptide.

8. PRO228

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD97, EMR1 and latrophilin, wherein the polypeptide is designated in the present application as “PRO228”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO228 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO228 polypeptide having amino acid residues 1 to 690 of FIG. 19 (SEQ ID NO:49), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO228 polypeptide. In particular, the invention provides isolated native sequence PRO228 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 690 of FIG. 19 (SEQ ID NO:49). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO228 polypeptide.

In another embodiment, the invention provides an expressed sequence tag (EST) comprising the nucleotide sequence of SEQ ID NO:50, designated herein as DNA21951.

9. PRO533

Applicants have identified a cDNA clone (DNA49435-1219) that encodes a novel polypeptide, designated in the present application as PRO533.

In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a DNA molecule encoding a PRO533 polypeptide comprising the sequence of amino acids 23 to 216 of FIG. 22 (SEQ ID NO:59), or (b) the complement of the DNA molecule of (a). The sequence identity preferably is about 85%, more preferably about 90%, most preferably about 95%. In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% sequence identity with a polypeptide having amino acid residues 23 to 216 of FIG. 22 (SEQ ID NO:59). Preferably, the highest degree of sequence identity occurs within the secreted portion (amino acids 23 to 216 of FIG. 22, SEQ ID NO:59). In a further embodiment, the isolated nucleic acid molecule comprises DNA encoding a PRO533 polypeptide having amino acid residues 1 to 216 of FIG. 22 (SEQ ID NO:59), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA49435-1219, deposited with the ATCC under accession number ATCC 209480.

In yet another embodiment, the invention provides isolated PRO533 polypeptide. In particular, the invention provides isolated native sequence PRO533 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 23 to 216 of FIG. 22 (SEQ ID NO:59). Native PRO533 polypeptides with or without the native signal sequence (amino acids 1 to 22 in FIG. 22 (SEQ ID NO:59)), and with or without the initiating methionine are specifically included. Alternatively, the invention provides a PRO533 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209480.

10. PRO245

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO245”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO245 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO245 polypeptide having amino acid residues 1 to 312 of FIG. 24 (SEQ ID NO:64), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO245 polypeptide. In particular, the invention provides isolated native sequence PRO245 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 312 of FIG. 24 (SEQ ID NO:64).

11. PRO220, PRO221 and PRO227

Applicants have identified cDNA clones that each encode novel polypeptides, all having leucine rich repeats. These polypeptides are designated in the present application as PRO220, PRO221 and PRO227.

In one embodiment, the invention provides isolated nucleic acid molecules comprising DNA respectively encoding PRO220, PRO221 and PRO227, respectively. In one aspect, provided herein is an isolated nucleic acid comprises DNA encoding the PRO220 polypeptide having amino acid residues 1 through 708 of FIG. 26 (SEQ ID NO:69), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. Also provided herein is an isolated nucleic acid comprises DNA encoding the PRO221 polypeptide having amino acid residues 1 through 259 of FIG. 28 (SEQ ID NO:71), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. Moreover, also provided herein is an isolated nucleic acid comprises DNA encoding the PRO227 polypeptide having amino acid residues 1 through 620 of FIG. 30 (SEQ ID NO:73), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO220, PRO221 and PRO227 polypeptides. In particular, provided herein is the isolated native sequence for the PRO220 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 708 of FIG. 26 (SEQ ID NO:69). Additionally provided herein is the isolated native sequence for the PRO221 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 259 of FIG. 28 (SEQ ID NO:71). Moreover, provided herein is the isolated native sequence for the PRO227 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 620 of FIG. 30 (SEQ ID NO:73).

12. PRO258

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CRTAM and poliovirus receptor precursors, wherein the polypeptide is designated in the present application as “PRO258”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO258 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO258 polypeptide having amino acid residues 1 to 398 of FIG. 32 (SEQ ID NO:84), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO258 polypeptide. In particular, the invention provides isolated native sequence PRO258 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 398 of FIG. 32 (SEQ ID NO:84). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO258 polypeptide.

13. PRO266

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO266”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO266 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO266 polypeptide having amino acid residues 1 to 696 of FIG. 34 (SEQ ID NO:91), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO266 polypeptide. In particular, the invention provides isolated native sequence PRO266 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 696 of FIG. 34 (SEQ ID NO:91).

14. PRO269

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as PRO269.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO269 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO269 polypeptide having amino acid residues 1 to 490 of FIG. 36 (SEQ ID NO:96), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO269 polypeptide. In particular, the invention provides isolated native sequence PRO269 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 490 of FIG. 36 (SEQ ID NO:96). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO269 polypeptide.

15. PRO287

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO287”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO287 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO287 polypeptide having amino acid residues 1 to 415 of FIG. 38 (SEQ ID NO:104), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO287 polypeptide. In particular, the invention provides isolated native sequence PRO287 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 415 of FIG. 38 (SEQ ID NO:104).

16. PRO214

Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as “PRO214”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO214 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO214 polypeptide of FIG. 40 (SEQ ID NO:109), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid comprising the coding sequence of FIG. 39 (SEQ ID NO:108) or its complement. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA32286-1191, deposited with ATCC under accession number ATCC 209385.

In yet another embodiment, the invention provides isolated PRO214 polypeptide. In particular, the invention provides isolated native sequence PRO214 polypeptide, which in one embodiment, includes an amino acid sequence comprising the residues of FIG. 40 (SEQ ID NO:109). Alternatively, the invention provides a polypeptide encoded by the nucleic acid deposited under accession number ATCC 209385.

17. PRO317

Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as “PRO317”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding PRO317 polypeptide. In one aspect, the isolated nucleic acid comprises DNA (SEQ ID NO:113) encoding PRO317 polypeptide having amino acid residues 1 to 366 of FIG. 42, or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO317 polypeptide. In particular, the invention provides isolated native-sequence PRO317 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 366 of FIG. 42 (SEQ ID NO:114).

In yet another embodiment, the invention supplies a method of detecting the presence of PRO317 in a sample, the method comprising:

a) contacting a detectable anti-PRO317 antibody with a sample suspected of containing PRO317; and

b) detecting binding of the antibody to the sample; wherein the sample is selected from the group consisting of a body fluid, a tissue sample, a cell extract, and a cell culture medium.

In a still further embodiment a method is provided for determining the presence of PRO317 mRNA in a sample, the method comprising:

a) contacting a sample suspected of containing PRO317 mRNA with a detectable nucleic acid probe that hybridizes under moderate to stringent conditions to PRO317 mRNA; and

b) detecting hybridization of the probe to the sample.

Preferably, in this method the sample is a tissue sample and the detecting step is by in situ hybridization, or the sample is a cell extract and detection is by Northern analysis.

Further, the invention provides a method for treating a PRO317-associated disorder comprising administering to a mammal an effective amount of the PRO317 polypeptide or a composition thereof containing a carrier, or with an effective amount of a PRO317 agonist or PRO317 antagonist, such as an antibody which binds specifically to PRO317.

18. PRO301

Applicants have identified a cDNA clone (DNA40628-1216) that encodes a novel polypeptide, designated in the present application as “PRO301”.

In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a DNA molecule encoding a PRO301 polypeptide comprising the sequence of amino acids 28 to 258 of FIG. 44 (SEQ ID NO:119), or (b) the complement of the DNA molecule of (a). The sequence identity preferably is about 85%, more preferably about 90%, most preferably about 95%. In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% sequence identity with a polypeptide having amino acid residues 28 to 258 of FIG. 44 (SEQ ID NO:119). Preferably, the highest degree of sequence identity occurs within the extracellular domains (amino acids 28 to 258 of FIG. 44, SEQ ID NO:119). In a further embodiment, the isolated nucleic acid molecule comprises DNA encoding a PRO301 polypeptide having amino acid residues 28 to 299 of FIG. 44 (SEQ ID NO:119), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA40628-1216, deposited with the ATCC under accession number ATCC 209432, alternatively the coding sequence of clone DNA40628-1216, deposited under accession number ATCC 209432.

In yet another embodiment, the invention provides isolated PRO301 polypeptide. In particular, the invention provides isolated native sequence PRO301 polypeptide, which in one embodiment, includes an amino acid sequence comprising the extracellular domain residues 28 to 258 of FIG. 44 (SEQ ID NO:119). Native PRO301 polypeptides with or without the native signal sequence (amino acids 1 to 27 in FIG. 44 (SEQ ID NO:119), and with or without the initiating methionine are specifically included. Additionally, the sequences of the invention may also comprise the transmembrane domain (residues 236 to about 258 in FIG. 44; SEQ ID NO:119) and/or the intracellular domain (about residue 259 to 299 in FIG. 44; SEQ ID NO:119). Alternatively, the invention provides a PRO301 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209432.

19. PRO224

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO224”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO224 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO224 polypeptide having amino acid residues 1 to 282 of FIG. 46 (SEQ ID NO:127), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO224 polypeptide. In particular, the invention provides isolated native sequence PRO224 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 282 of FIG. 46 (SEQ ID NO:127).

20. PRO222

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO222”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO222 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO222 polypeptide having amino acid residues 1 to 490 of FIG. 48 (SEQ ID NO:132), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO222 polypeptide. In particular, the invention provides isolated native sequence PRO222 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 490 of FIG. 48 (SEQ ID NO:132).

21. PRO234

Applicants have identified a cDNA clone that encodes a novel lectin polypeptide molecule, designated in the present application as “PRO234”.

In one embodiment, the invention provides an isolated nucleic acid encoding a novel lectin comprising DNA encoding a PRO234 polypeptide. In one aspect, the isolated nucleic acid comprises the DNA encoding PRO234 polypeptides having amino acid residues 1 to 382 of FIG. 50 (SEQ ID NO:137), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides an isolated nucleic acid molecule comprising the nucleotide sequence of FIG. 49 (SEQ ID NO:136).

In another embodiment, the invention provides isolated novel PRO234 polypeptides. In particular, the invention provides isolated native sequence PRO234 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 382 of FIG. 50 (SEQ ID NO:137).

In yet another embodiment, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences.

22. PRO231

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to a putative acid phosphatase, wherein the polypeptide is designated in the present application as “PRO231”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO231 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO231 polypeptide having amino acid residues 1 to 428 of FIG. 52 (SEQ ID NO:142), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO231 polypeptide. In particular, the invention provides isolated native sequence PRO231 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 428 of FIG. 52 (SEQ ID NO:142).

23. PRO229

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to scavenger receptors wherein the polypeptide is designated in the present application as “PRO229”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO229 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO229 polypeptide having amino acid residues 1 to 347 of FIG. 54 (SEQ ID NO:148), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO229 polypeptide. In particular, the invention provides isolated native sequence PRO229 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 347 of FIG. 54 (SEQ ID NO:148).

24. PRO238

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to reductase, wherein the polypeptide is designated in the present application as “PRO238”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO238 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO238 polypeptide having amino acid-residues 1 to 310 of FIG. 56 (SEQ ID NO:153), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO238 polypeptide. In particular, the invention provides isolated native sequence PRO238 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 310 of FIG. 56 (SEQ ID NO:153).

25. PRO233

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO233”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO233 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO233 polypeptide having amino acid residues 1 to 300 of FIG. 58 (SEQ ID NO:159), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO233 polypeptide. In particular, the invention provides isolated native sequence PRO233 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 300 of FIG. 58 (SEQ ID NO:159).

26. PRO223

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to serine carboxypeptidase polypeptides, wherein the polypeptide is designated in the present application as “PRO223”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO223 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO223 polypeptide having amino acid residues 1 to 476 of FIG. 60 (SEQ ID NO:164), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO223 polypeptide. In particular, the invention provides isolated native sequence PRO223 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 476 of FIG. 60 (SEQ ID NO:164).

27. PRO235

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO235”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO235 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO235 polypeptide having amino acid residues 1 to 552 of FIG. 62 (SEQ ID NO:170), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO235 polypeptide. In particular, the invention provides isolated native sequence PRO235 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 552 of FIG. 62 (SEQ ID NO:170).

28. PRO236 and PRO262

Applicants have identified cDNA clones that encode novel polypeptides having homology to β-galactosidase, wherein those polypeptides are designated in the present application as “PRO236” and “PRO262”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO236 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO236 polypeptide having amino acid residues 1 to 636 of FIG. 64 (SEQ ID NO:175), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO262 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO262 polypeptide having amino acid residues 1 to 654 of FIG. 66 (SEQ ID NO:177), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO236 polypeptide. In particular, the invention provides isolated native sequence PRO236 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 636 of FIG. 64 (SEQ ID NO:175).

In another embodiment, the invention provides isolated PRO262 polypeptide. In particular, the invention provides isolated native sequence PRO262 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 654 of FIG. 66 (SEQ ID NO:177).

29. PRO239

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO239”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO239 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO239 polypeptide having amino acid residues 1 to 501 of FIG. 68 (SEQ ID NO:185), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO239 polypeptide. In particular, the invention provides isolated native sequence PRO239 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 501 of FIG. 68 (SEQ ID NO:185).

30. PRO257

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO257”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO257 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO257 polypeptide having amino acid residues 1 to 607 of FIG. 70 (SEQ ID NO:190), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO257 polypeptide. In particular, the invention provides isolated native sequence PRO257 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 607 of FIG. 70 (SEQ ID NO:190). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO257 polypeptide.

31. PRO260

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO260”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO260 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO260 polypeptide having amino acid residues 1 to 467 of FIG. 72 (SEQ ID NO:195), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO260 polypeptide. In particular, the invention provides isolated native sequence PRO260 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 467 of FIG. 72 (SEQ ID NO:195).

32. PRO263

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to CD44 antigen, wherein the polypeptide is designated in the present application as “PRO263”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO263 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO263 polypeptide having amino acid residues 1 to 322 of FIG. 74 (SEQ ID NO:201), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO263 polypeptide. In particular, the invention provides isolated native sequence PRO263 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 322 of FIG. 74 (SEQ ID NO:201). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO263 polypeptide.

33. PRO270

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO270”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO270 polypeptide. In one aspect, the isolated nucleic acid comprises DNA which includes the sequence encoding the PRO270 polypeptide having amino acid residues 1 to 296 of FIG. 76 (SEQ ID NO:207), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO270 polypeptide. In particular, the invention provides isolated native sequence PRO270 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 296 of FIG. 76 (SEQ ID NO:207).

34. PRO271

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the proteoglycan link protein, wherein the polypeptide is designated in the present application as “PRO271”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO271 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO271 polypeptide having amino acid residues 1 to 360 of FIG. 78 (SEQ ID NO:213), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO271 polypeptide. In particular, the invention provides isolated native sequence PRO271 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 360 of FIG. 78 (SEQ ID NO:213).

35. PRO272

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO272”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO272 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO272 polypeptide having amino acid residues 1 to 328 of FIG. 80 (SEQ ID NO:221), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO272 polypeptide. In particular, the invention provides isolated native sequence PRO272 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 328 of FIG. 80 (SEQ ID NO:211).

36. PRO294

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO294”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO294 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO294 polypeptide having amino acid residues 1 to 550 of FIG. 82 (SEQ ID NO:227), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO294 polypeptide. In particular, the invention provides isolated native sequence PRO294 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 550 of FIG. 82 (SEQ ID NO:227).

37. PRO295

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO295”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO295 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO295 polypeptide having amino acid residues 1 to 350 of FIG. 84 (SEQ ID NO:236), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO295 polypeptide. In particular, the invention provides isolated native sequence PRO295 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 350 of FIG. 84 (SEQ ID NO:236).

38. PRO293

Applicants have identified a cDNA clone that encodes a novel human neuronal leucine rich repeat polypeptide, wherein the polypeptide is designated in the present application as “PRO293”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO293 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO293 polypeptide having amino acid residues 1 to 713 of FIG. 86 (SEQ ID NO:245), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO293 polypeptide. In particular, the invention provides isolated native sequence PRO293 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 713 of FIG. 86 (SEQ ID NO:245). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO293 polypeptide.

39. PRO247

Applicants have identified a cDNA clone that encodes a novel polypeptide having leucine rich repeats wherein the polypeptide is designated in the present application as “PRO247”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO247 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO247 polypeptide having amino acid residues 1 to 546 of FIG. 88 (SEQ ID NO:250), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO247 polypeptide. In particular, the invention provides isolated native sequence PRO247 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 546 of FIG. 88 (SEQ ID NO:250). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO247 polypeptide.

40. PRO302, PRO303, PRO304, PRO307 and PRO343

Applicants have identified cDNA clones that encode novel polypeptides having homology to various proteases, wherein those polypeptide are designated in the present application as “PRO302”, “PRO303”, “PRO304”, “PRO307” and “PRO343” polypeptides.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO302 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO302 polypeptide having amino acid residues 1 to 452 of FIG. 90 (SEQ ID NO:255), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO303 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO303 polypeptide having amino acid residues 1 to 314 of FIG. 92 (SEQ ID NO:257), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In yet another embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO304 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO304 polypeptide having amino acid residues 1 to 556 of FIG. 94 (SEQ ID NO:259), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO307 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO307 polypeptide having amino acid residues 1 to 383 of FIG. 96 (SEQ ID NO:261), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO343 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO343 polypeptide having amino acid residues 1 to 317 of FIG. 98 (SEQ ID NO:263), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO302 polypeptide. In particular, the invention provides isolated native sequence PRO302 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 452 of FIG. 90 (SEQ ID NO:255).

In another embodiment, the invention provides isolated PRO303 polypeptide. In particular, the invention provides isolated native sequence PRO303 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 314 of FIG. 92 (SEQ ID NO:257).

In another embodiment, the invention provides isolated PRO304 polypeptide. In particular, the invention provides isolated native sequence PRO304 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 556 of FIG. 94 (SEQ ID NO:259).

In another embodiment, the invention provides isolated PRO307 polypeptide. In particular, the invention provides isolated native sequence PRO307 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 383 of FIG. 96 (SEQ ID NO:261).

In another embodiment, the invention provides isolated PRO343 polypeptide. In particular, the invention provides isolated native sequence PRO343 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 317 of FIG. 98 (SEQ ID NO:263).

41. PRO328

Applicants have identified a cDNA clone that encodes a novel polypeptide, wherein the polypeptide is designated in the present application as “PRO328”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO328 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO328 polypeptide having amino acid residues 1 to 463 of FIG. 100 (SEQ ID NO:285), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO328 polypeptide. In particular, the invention provides isolated native sequence PRO328 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 463 of FIG. 100 (SEQ ID NO:285). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO306 polypeptide.

42. PRO335, PRO331 and PRO326

Applicants have identified three cDNA clones that respectively encode three novel polypeptides, each having leucine rich repeats and homology to LIG-1 and ALS. These polypeptides are designated in the present application as PRO335, PRO331 and PRO326, respectively.

In one embodiment, the invention provides three isolated nucleic acid molecules comprising DNA respectively encoding PRO335, PRO331 and PRO326, respectively. In one aspect, herein is provided an isolated nucleic acid comprising DNA encoding the PRO335 polypeptide having amino acid residues 1 through 1059 of FIG. 102 (SEQ ID NO:290), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. Also provided herein is an isolated nucleic acid comprises DNA encoding the PRO331 polypeptide having amino acid residues 1 through 640 of FIG. 104 (SEQ ID NO:292), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. Additionally provided herein is an isolated nucleic acid comprises DNA encoding the PRO326 polypeptide having amino acid residues 1 through 1119 of FIG. 106 (SEQ ID NO:294), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO335, PRO331 and PRO326 polypeptides or extracellular domains thereof. In particular, the invention provides isolated native sequence for the PRO335 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 1059 of FIG. 102 (SEQ ID NO:290). Also provided herein is the isolated native sequence for the PRO331 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 640 of FIG. 104 (SEQ ID NO:292). Also provided herein is the isolated native sequence for the PRO326 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 through 1119 of FIG. 106 (SEQ ID NO:294).

43. PRO332

Applicants have identified a cDNA clone (DNA40982-1235) that encodes a novel polypeptide, designated in the present application as “PRO332.”

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA having at least about 80% sequence identity to (a) a DNA molecule encoding a PRO358 polypeptide comprising the sequence of amino acids 49 to 642 of FIG. 108 (SEQ ID NO:310), or (b) the complement of the DNA molecule of (a). The sequence identity preferably is about 85%, more preferably about 90%, most preferably about 95%. In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% sequence identity with a polypeptide having amino acid residues 1 to 642 of FIG. 108 (SEQ ID NO:310). Preferably, the highest degree of sequence identity occurs within the leucine-rich repeat domains (amino acids 116 to 624 of FIG. 108, SEQ ID NO:310). In a further embodiment, the isolated nucleic acid molecule comprises DNA encoding a PRO332 polypeptide having amino acid residues 49 to 642 of FIG. 108 (SEQ ID NO:310), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO332 polypeptides. In particular, the invention provides isolated native sequence PRO332 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 49 to 624 of FIG. 108 (SEQ ID NO:310). Native PRO332 polypeptides with or without the native signal sequence (amino acids 1 to 48 in FIG. 108, SEQ ID NO:310), and with or without the initiating methionine are specifically included.

44. PRO334

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to fibulin and fibrillin, wherein the polypeptide is designated in the present application as “PRO334”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO334 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO334 polypeptide having amino acid residues 1 to 509 of FIG. 110 (SEQ ID NO:315), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO334 polypeptide. In particular, the invention provides isolated native sequence PRO334 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 509 of FIG. 110 (SEQ ID NO:315).

45. PRO346

Applicants have identified a cDNA clone (DNA44167-1243) that encodes a novel polypeptide, designated in the present application as “PRO346.”

In one embodiment, the invention provides an isolated nucleic acid molecule having at least about 80% sequence identity to (a) a DNA molecule encoding a PRO346 polypeptide comprising the sequence of amino acids 19 to 339 of FIG. 112 (SEQ ID NO:320), or (b) the complement of the DNA molecule of (a). The sequence identity preferably is about 85%, more preferably about 90%, most preferably about 95%. In one aspect, the isolated nucleic acid has at least about 80%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% sequence identity with a polypeptide having amino acid residues 19 to 339 of FIG. 112 (SEQ ID NO:320). Preferably, the highest degree of sequence identity occurs within the extracellular domains (amino acids 19 to 339 of FIG. 112, SEQ ID NO:320). In alternative embodiments, the polypeptide by which the homology is measured comprises the residues 1-339, 19-360 or 19-450 of FIG. 112, SEQ ID NO:320). In a further embodiment, the isolated nucleic acid molecule comprises DNA encoding a PRO346 polypeptide having amino acid residues 19 to 339 of FIG. 112 (SEQ ID NO:320), alternatively residues 1-339, 19-360 or 19-450 of FIG. 112 (SEQ ID NO:320) or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the invention provides a nucleic acid of the full length protein of clone DNA44167-1243, deposited with the ATCC under accession number ATCC 209434, alternatively the coding sequence of clone DNA44167-1243, deposited under accession number ATCC 209434.

In yet another embodiment, the invention provides isolated PRO346 polypeptide. In particular, the invention provides isolated native sequence PRO346 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 19 to 339 of FIG. 112 (SEQ ID NO:320). Native PRO346 polypeptides with or without the native signal sequence (residues 1 to 18 in FIG. 112 (SEQ ID NO:320), with or without the initiating methionine, with or without the transmembrane domain (residues 340 to 360) and with or without the intracellular domain (residues 361 to 450) are specifically included. Alternatively, the invention provides a PRO346 polypeptide encoded by the nucleic acid deposited under accession number ATCC 209434.

46. PRO268

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to protein disulfide isomerase, wherein the polypeptide is designated in the present application as “PRO268”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO268 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO268 polypeptide having amino acid residues 1 to 280 of FIG. 114 (SEQ ID NO:325), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO268 polypeptide. In particular, the invention provides isolated native sequence PRO268 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 280 of FIG. 114 (SEQ ID NO:325). An additional embodiment of the present invention is directed to an isolated extracellular domain of a PRO268 polypeptide.

47. PRO330

Applicants have identified a cDNA clone that encodes a novel polypeptide having homology to the alpha subunit of prolyl 4-hydroxylase, wherein the polypeptide is designated in the present application as “PRO330”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding a PRO330 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO330 polypeptide having amino acid residues 1 to 533 of FIG. 116 (SEQ ID NO:332), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO330 polypeptide. In particular, the invention provides isolated native sequence PRO330 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 533 of FIG. 116 (SEQ ID NO:332).

48. PRO339 and PRO310

Applicants have identified two cDNA clones wherein each clone encodes a novel polypeptide having homology to fringe, wherein the polypeptides are designated in the present application as “PRO339” and “PRO310”.

In one embodiment, the invention provides isolated nucleic acid molecules comprising DNA encoding a PRO339 and/or a PRO310 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding the PRO339 polypeptide having amino acid residues 1 to 772 of FIG. 118 (SEQ ID NO:339), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions. In another aspect, the isolated nucleic acid comprises DNA encoding the PRO310 polypeptide having amino acid residues 1 to 318 of FIG. 120 (SEQ ID NO:341), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO339 as well as isolated PRO310 polypeptides. In particular, the invention provides isolated native sequence PRO339 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 772 of FIG. 118 (SEQ ID NO:339). The invention further provides isolated native sequence PRO3 10 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 318 of FIG. 120 (SEQ ID NO:341).

49. PRO244

Applicants have identified a cDNA clone that encodes a novel polypeptide, designated in the present application as “PRO244”.

In one embodiment, the invention provides an isolated nucleic acid molecule comprising DNA encoding PRO244 polypeptide. In one aspect, the isolated nucleic acid comprises DNA encoding PRO244 polypeptide having amino acid residues 1 to 219 of FIG. 122 (SEQ ID NO:377), or is complementary to such encoding nucleic acid sequence, and remains stably bound to it under at least moderate, and optionally, under high stringency conditions.

In another embodiment, the invention provides isolated PRO244 polypeptide. In particular, the invention provides isolated native sequence PRO244 polypeptide, which in one embodiment, includes an amino acid sequence comprising residues 1 to 219 of FIG. 122 (SEQ ID NO:377).

50. Additional Embodiments

In other embodiments of the present invention, the invention provides vectors comprising DNA encoding any of the herein described polypeptides. Host cell comprising any such vector are also provided. By way of example, the host cells may be CHO cells, E. coli, or yeast. A process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.

In other embodiments, the invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence. Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.

In another embodiment, the invention provides an antibody which specifically binds to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.

In yet other embodiments, the invention provides oligonucleotide probes useful for isolating genomic and cDNA nucleotide sequences, wherein those probes may be derived from any of the above or below described nucleotide sequences.

In other embodiments, the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO polypeptide.

In one aspect, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to (a) a DNA molecule encoding a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein or an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein, or (b) the complement of the DNA molecule of (a).

In other aspects, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to (a) a DNA molecule comprising the coding sequence of a full-length PRO polypeptide cDNA as disclosed herein, the coding sequence of a PRO polypeptide lacking the signal peptide as disclosed herein or the coding sequence of an extracellular domain of a transmembrane PRO polypeptide, with or without the signal peptide, as disclosed herein, or (b) the complement of the DNA molecule of (a).

In a further aspect, the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to (a) a DNA molecule that encodes the same mature polypeptide encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein, or (b) the complement of the DNA molecule of (a).

Another aspect the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO polypeptides are contemplated.

Another embodiment is directed to fragments of a PRO polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes or for encoding fragments of a PRO polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO antibody. Such nucleic acid fragments are usually at least about 20 nucleotides in length, preferably at least about 30 nucleotides in length, more preferably at least about 40 nucleotides in length, yet more preferably at least about 50 nucleotides in length, yet more preferably at least about 60 nucleotides in length, yet more preferably at least about 70 nucleotides in length, yet more preferably at least about 80 nucleotides in length, yet more preferably at least about 90 nucleotides in length, yet more preferably at least about 100 nucleotides in length, yet more preferably at least about 110 nucleotides in length, yet more preferably at least about 120 nucleotides in length, yet more preferably at least about 130 nucleotides in length, yet more preferably at least about 140 nucleotides in length, yet more preferably at least about 150 nucleotides in length, yet more preferably at least about 160 nucleotides in length, yet more preferably at least about 170 nucleotides in length, yet more preferably at least about 180 nucleotides in length, yet more preferably at least about 190 nucleotides in length, yet more preferably at least about 200 nucleotides in length, yet more preferably at least about 250 nucleotides in length, yet more preferably at least about 300 nucleotides in length, yet more preferably at least about 350 nucleotides in length, yet more preferably at least about 400 nucleotides in length, yet more preferably at least about 450 nucleotides in length, yet more preferably at least about 500 nucleotides in length, yet more preferably at least about 600 nucleotides in length, yet more preferably at least about 700 nucleotides in length, yet more preferably at least about 800 nucleotides in length, yet more preferably at least about 900 nucleotides in length and yet more preferably at least about 1000 nucleotides in length, wherein in this context the term “about” means the referenced nucleotide sequence length plus or minus 10% of that referenced length. It is noted that novel fragments of a PRO polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO polypeptide-encoding nucleotide sequence with other known nucleotide sequences using any of a number of well known sequence alignment programs and determining which PRO polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO polypeptide fragments that comprise a binding site for an anti-PRO antibody.

In another embodiment, the invention provides isolated PRO polypeptide encoded by any of the isolated nucleic acid sequences hereinabove identified.

In a certain aspect, the invention concerns an isolated PRO polypeptide, comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein or an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptide comprising an amino acid sequence having at least about 80% sequence identity, preferably at least about 81% sequence identity, more preferably at least about 82% sequence identity, yet more preferably at least about 83% sequence identity, yet more preferably at least about 84% sequence identity, yet more preferably at least about 85% sequence identity, yet more preferably at least about 86% sequence identity, yet more preferably at least about 87% sequence identity, yet more preferably at least about 88% sequence identity, yet more preferably at least about 89% sequence identity, yet more preferably at least about 90% sequence identity, yet more preferably at least about 91% sequence identity, yet more preferably at least about 92% sequence identity, yet more preferably at least about 93% sequence identity, yet more preferably at least about 94% sequence identity, yet more preferably at least about 95% sequence identity, yet more preferably at least about 96% sequence identity, yet more preferably at least about 97% sequence identity, yet more preferably at least about 98% sequence identity and yet more preferably at least about 99% sequence identity to an amino acid sequence encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein.

In a further aspect, the invention concerns an isolated PRO polypeptide comprising an amino acid sequence scoring at least about 80% positives, preferably at least about 81% positives, more preferably at least about 82% positives, yet more preferably at least about 83% positives, yet more preferably at least about 84% positives, yet more preferably at least about 85% positives, yet more preferably at least about 86% positives, yet more preferably at least about 87% positives, yet more preferably at least about 88% positives, yet more preferably at least about 89% positives, yet more preferably at least about 90% positives, yet more preferably at least about 91% positives, yet more preferably at least about 92% positives, yet more preferably at least about 93% positives, yet more preferably at least about 94% positives, yet more preferably at least about 95% positives, yet more preferably at least about 96% positives, yet more preferably at least about 97% positives, yet more preferably at least about 98% positives and yet more preferably at least about 99% positives when compared with the amino acid sequence of a PRO polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein or an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein.

In a specific aspect, the invention provides an isolated PRO polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.

Another aspect the invention provides an isolated PRO polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO polypeptide and recovering the PRO polypeptide from the cell culture.

In yet another embodiment, the invention concerns agonists and antagonists of a native PRO polypeptide as defined herein. In a particular embodiment, the agonist or antagonist is an anti-PRO antibody or a small molecule.

In a further embodiment, the invention concerns a method of identifying agonists or antagonists to a PRO polypeptide which comprise contacting the PRO polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO polypeptide. Preferably, the PRO polypeptide is a native PRO polypeptide.

In a still further embodiment, the invention concerns a composition of matter comprising a PRO polypeptide, or an agonist or antagonist of a PRO polypeptide as herein described, or an anti-PRO antibody, in combination with a carrier. Optionally, the carrier is a pharmaceutically acceptable carrier.

Another embodiment of the present invention is directed to the use of a PRO polypeptide, or an agonist or antagonist thereof as hereinbefore described, or an anti-PRO antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the PRO polypeptide, an agonist or antagonist thereof or an anti-PRO antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PRO211 cDNA, wherein SEQ ID NO:1 is a clone designated herein as “DNA32292-1131”.

FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO:1 shown in FIG. 1.

FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequence PRO217 cDNA, wherein SEQ ID NO:3 is a clone designated herein as “DNA33094-1131”.

FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO:3 shown in FIG. 3.

FIG. 5 shows a nucleotide sequence (SEQ ID NO:11) of a native sequence PRO230 cDNA, wherein SEQ ID NO:11 is a clone designated herein as “DNA33223-1136”.

FIG. 6 shows the amino acid sequence (SEQ ID NO:12) derived from the coding sequence of SEQ ID NO:11 shown in FIG. 5.

FIG. 7 shows a nucleotide sequence designated herein as DNA20088 (SEQ ID NO:13).

FIG. 8 shows a nucleotide sequence (SEQ ID NO:17) of a native sequence PRO232 cDNA, wherein SEQ ID NO:17 is a clone designated herein as “DNA34435-1140”.

FIG. 9 shows the amino acid sequence (SEQ ID NO:18) derived from the coding sequence of SEQ ID NO:17 shown in FIG. 8.

FIG. 10 shows a nucleotide sequence (SEQ ID NO:22) of a native sequence PRO187 cDNA, wherein SEQ ID NO:22 is a clone designated herein as “DNA27864-1155”.

FIG. 11 shows the amino acid sequence (SEQ ID NO:23) derived from the coding sequence of SEQ ID NO:22 shown in FIG. 10.

FIG. 12 shows a nucleotide sequence (SEQ ID NO:27) of a native sequence PRO265 cDNA, wherein SEQ ID NO:27 is a clone designated herein as “DNA36350-1158”.

FIG. 13 shows the amino acid sequence (SEQ ID NO:28) derived from the coding sequence of SEQ ID NO:27 shown in FIG. 12.

FIG. 14 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PRO219 cDNA, wherein SEQ ID NO:33 is a clone designated herein as “DNA32290-1164”.

FIG. 15 shows the amino acid sequence (SEQ ID NO:34) derived from the coding sequence of SEQ ID NO:33 shown in FIG. 14.

FIG. 16 shows a nucleotide sequence (SEQ ID NO:38) of a native sequence PRO246 cDNA, wherein SEQ ID NO:38 is a clone designated herein as “DNA35639-1172”.

FIG. 17 shows the amino acid sequence (SEQ ID NO:39) derived from the coding sequence of SEQ ID NO:38 shown in FIG. 16.

FIG. 18 shows a nucleotide sequence (SEQ ID NO:48) of a native sequence PRO228 cDNA, wherein SEQ ID NO:48 is a clone designated herein as “DNA33092-1202”.

FIG. 19 shows the amino acid sequence (SEQ ID NO:49) derived from the coding sequence of SEQ ID NO:48 shown in FIG. 18.

FIG. 20 shows a nucleotide sequence designated herein as DNA21951 (SEQ ID NO:50).

FIG. 21 shows a nucleotide sequence (SEQ ID NO:58) of a native sequence PRO533 cDNA, wherein SEQ ID NO:58 is a clone designated herein as “DNA49435-1219”.

FIG. 22 shows the amino acid sequence (SEQ ID NO:59) derived from the coding sequence of SEQ ID NO:58 shown in FIG. 21.

FIG. 23 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PRO245 cDNA, wherein SEQ ID NO:63 is a clone designated herein as “DNA35638-1141”.

FIG. 24 shows the amino acid sequence (SEQ ID NO:64) derived from the coding sequence of SEQ ID NO:63 shown in FIG. 23.

FIG. 25 shows a nucleotide sequence (SEQ ID NO:68) of a native sequence PRO220 cDNA, wherein SEQ ID NO:68 is a clone designated herein as “DNA32298-1132”.

FIG. 26 shows the amino acid sequence (SEQ ID NO:69) derived from the coding sequence of SEQ ID NO:68 shown in FIG. 25.

FIG. 27 shows a nucleotide sequence (SEQ ID NO:70) of a native sequence PRO221 cDNA, wherein SEQ ID NO:70 is a clone designated herein as “DNA33089-1132”.

FIG. 28 shows the amino acid sequence (SEQ ID NO:71) derived from the coding sequence of SEQ ID NO:70 shown in FIG. 27.

FIG. 29 shows a nucleotide sequence (SEQ ID NO:72) of a native sequence PRO227 cDNA, wherein SEQ ID NO:72 is a clone designated herein as “DNA33786-1132”.

FIG. 30 shows the amino acid sequence (SEQ ID NO:73) derived from the coding sequence of SEQ ID NO:72 shown in FIG. 29.

FIG. 31 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PRO258 cDNA, wherein SEQ ID NO:83 is a clone designated herein as “DNA35918-1174”.

FIG. 32 shows the amino acid sequence (SEQ ID NO:84) derived from the coding sequence of SEQ ID NO:83 shown in FIG. 31.

FIG. 33 shows a nucleotide sequence (SEQ ID NO:90) of a native sequence PRO266 cDNA, wherein SEQ ID NO:90 is a clone designated herein as “DNA37150-1178”.

FIG. 34 shows the amino acid sequence (SEQ ID NO:91) derived from the coding sequence of SEQ ID NO:90 shown in FIG. 33.

FIG. 35 shows a nucleotide sequence (SEQ ID NO:95) of a native sequence PRO269 cDNA, wherein SEQ ID NO:95 is a clone designated herein as “DNA38260-1180”.

FIG. 36 shows the amino acid sequence (SEQ ID NO:96) derived from the coding sequence of SEQ ID NO:95 shown in FIG. 35.

FIG. 37 shows a nucleotide sequence (SEQ ID NO:103) of a native sequence PRO287 cDNA, wherein SEQ ID NO:103 is a clone designated herein as “DNA39969-1185”.

FIG. 38 shows the amino acid sequence (SEQ ID NO:104) derived from the coding sequence of SEQ ID NO:103 shown in FIG. 37.

FIG. 39 shows a nucleotide sequence (SEQ ID NO:108) of a native sequence PRO214 cDNA, wherein SEQ ID NO:108 is a clone designated herein as “DNA32286-1191”.

FIG. 40 shows the amino acid sequence (SEQ ID NO:109) derived from the coding sequence of SEQ ID NO:108 shown in FIG. 39.

FIG. 41 shows a nucleotide sequence (SEQ ID NO:113) of a native sequence PRO317 cDNA, wherein SEQ ID NO:113 is a clone designated herein as “DNA33461-1199”.

FIG. 42 shows the amino acid sequence (SEQ ID NO:114) derived from the coding sequence of SEQ ID NO:113 shown in FIG. 41.

FIG. 43 shows a nucleotide sequence (SEQ ID NO:118) of a native sequence PRO301 cDNA, wherein SEQ ID NO:118 is a clone designated herein as “DNA40628-1216”.

FIG. 44 shows the amino acid sequence (SEQ ID NO:119) derived from the coding sequence of SEQ ID NO:118 shown in FIG. 43.

FIG. 45 shows a nucleotide sequence (SEQ ID NO:126) of a native sequence PRO224 cDNA, wherein SEQ ID NO:126 is a clone designated herein as “DNA33221-1133”.

FIG. 46 shows the amino acid sequence (SEQ ID NO:127) derived from the coding sequence of SEQ ID NO:126 shown in FIG. 45.

FIG. 47 shows a nucleotide sequence (SEQ ID NO:131) of a native sequence PRO222 cDNA, wherein SEQ ID NO:131 is a clone designated herein as “DNA33107-1135”.

FIG. 48 shows the amino acid sequence (SEQ ID NO:132) derived from the coding sequence of SEQ ID NO:131 shown in FIG. 47.

FIG. 49 shows a nucleotide sequence (SEQ ID NO:136) of a native sequence PRO234 cDNA, wherein SEQ ID NO:136 is a clone designated herein as “DNA35557-1137”.

FIG. 50 shows the amino acid sequence (SEQ ID NO:137) derived from the coding sequence of SEQ ID NO:136 shown in FIG. 49.

FIG. 51 shows a nucleotide sequence (SEQ ID NO:141) of a native sequence PRO231 cDNA, wherein SEQ ID NO:141 is a clone designated herein as “DNA34434-1139”.

FIG. 52 shows the amino acid sequence (SEQ ID NO:142) derived from the coding sequence of SEQ ID NO:141 shown in FIG. 51.

FIG. 53 shows a nucleotide sequence (SEQ ID NO:147) of a native sequence PRO229 cDNA, wherein SEQ ID NO:147 is a clone designated herein as “DNA33100-1159”.

FIG. 54 shows the amino acid sequence (SEQ ID NO:148) derived from the coding sequence of SEQ ID NO:147 shown in FIG. 53.

FIG. 55 shows a nucleotide sequence (SEQ ID NO:152) of a native sequence PRO238 cDNA, wherein SEQ ID NO:152 is a clone designated herein as “DNA35600-1162”.

FIG. 56 shows the amino acid sequence (SEQ ID NO:153) derived from the coding sequence of SEQ ID NO:152 shown in FIG. 55.

FIG. 57 shows a nucleotide sequence (SEQ ID NO:158) of a native sequence PRO233 cDNA, wherein SEQ ID NO:158 is a clone designated herein as “DNA34436-1238”.

FIG. 58 shows the amino acid sequence (SEQ ID NO:159) derived from the coding sequence of SEQ ID NO:158 shown in FIG. 57.

FIG. 59 shows a nucleotide sequence (SEQ ID NO:163) of a native sequence PRO223 cDNA, wherein SEQ ID NO:163 is a clone designated herein as “DNA33206-1165”.

FIG. 60 shows the amino acid sequence (SEQ ID NO:164) derived from the coding sequence of SEQ ID NO:163 shown in FIG. 59.

FIG. 61 shows a nucleotide sequence (SEQ ID NO:169) of a native sequence PRO235 cDNA, wherein SEQ ID NO:169 is a clone designated herein as “DNA35558-1167”.

FIG. 62 shows the amino acid sequence (SEQ ID NO:170) derived from the coding sequence of SEQ ID NO:169 shown in FIG. 61.

FIG. 63 shows a nucleotide sequence (SEQ ID NO:174) of a native sequence PRO236 cDNA, wherein SEQ ID NO:174 is a clone designated herein as “DNA35599-1168”.

FIG. 64 shows the amino acid sequence (SEQ ID NO:175) derived from the coding sequence of SEQ ID NO:174 shown in FIG. 63.

FIG. 65 shows a nucleotide sequence (SEQ ID NO:176) of a native sequence PRO262 cDNA, wherein SEQ ID NO:176 is a clone designated herein as “DNA36992-1168”.

FIG. 66 shows the amino acid sequence (SEQ ID NO:177) derived from the coding sequence of SEQ ID NO:176 shown in FIG. 65.

FIG. 67 shows a nucleotide sequence (SEQ ID NO:184) of a native sequence PRO239 cDNA, wherein SEQ ID NO:184 is a clone designated herein as “DNA34407-1169”.

FIG. 68 shows the amino acid sequence (SEQ ID NO:185) derived from the coding sequence of SEQ ID NO:184 shown in FIG. 67.

FIG. 69 shows a nucleotide sequence (SEQ ID NO:189) of a native sequence PRO257 cDNA, wherein SEQ ID NO:189 is a clone designated herein as “DNA35841-1173”.

FIG. 70 shows the amino acid sequence (SEQ ID NO:190) derived from the coding sequence of SEQ ID NO:189 shown in FIG. 69.

FIG. 71 shows a nucleotide sequence (SEQ ID NO:194) of a native sequence PRO260 cDNA, wherein SEQ ID NO:194 is a clone designated herein as “DNA33470-1175”.

FIG. 72 shows the amino acid sequence (SEQ ID NO:195) derived from the coding sequence of SEQ ID NO:194 shown in FIG. 71.

FIG. 73 shows a nucleotide sequence (SEQ ID NO:200) of a native sequence PRO263 cDNA, wherein SEQ ID NO:200 is a clone designated herein as “DNA34431-1177”.

FIG. 74 shows the amino acid sequence (SEQ ID NO:201) derived from the coding sequence of SEQ ID NO:200 shown in FIG. 73.

FIG. 75 shows a nucleotide sequence (SEQ ID NO:206) of a native sequence PRO270 cDNA, wherein SEQ ID NO:206 is a clone designated herein as “DNA39510-1181”.

FIG. 76 shows the amino acid sequence (SEQ ID NO:207) derived from the coding sequence of SEQ ID NO:206 shown in FIG. 75.

FIG. 77 shows a nucleotide sequence (SEQ ID NO:212) of a native sequence PRO271 cDNA, wherein SEQ ID NO:212 is a clone designated herein as “DNA39423-1182”.

FIG. 78 shows the amino acid sequence (SEQ ID NO:213) derived from the coding sequence of SEQ ID NO:212 shown in FIG. 77.

FIG. 79 shows a nucleotide sequence (SEQ ID NO:220) of a native sequence PRO272 cDNA, wherein SEQ ID NO:220 is a clone designated herein as “DNA40620-1183”.

FIG. 80 shows the amino acid sequence (SEQ ID NO:221) derived from the coding sequence of SEQ ID NO:220 shown in FIG. 79.

FIG. 81 shows a nucleotide sequence (SEQ ID NO:226) of a native sequence PRO294 cDNA, wherein SEQ ID NO:226 is a clone designated herein as “DNA40604-1187”.

FIG. 82 shows the amino acid sequence (SEQ ID NO:227) derived from the coding sequence of SEQ ID NO:226 shown in FIG. 81.

FIG. 83 shows a nucleotide sequence (SEQ ID NO:235) of a native sequence PRO295 cDNA, wherein SEQ ID NO:235 is a clone designated herein as “DNA38268-1188”.

FIG. 84 shows the amino acid sequence (SEQ ID NO:236) derived from the coding sequence of SEQ ID NO:235 shown in FIG. 83.

FIG. 85 shows a nucleotide sequence (SEQ ID NO:244) of a native sequence PRO293 cDNA, wherein SEQ ID NO:244 is a clone designated herein as “DNA37151-1193”.

FIG. 86 shows the amino acid sequence (SEQ ID NO:245) derived from the coding sequence of SEQ ID NO:244 shown in FIG. 85.

FIG. 87 shows a nucleotide sequence (SEQ ID NO:249) of a native sequence PRO247 cDNA, wherein SEQ ID NO:249 is a clone designated herein as “DNA35673-1201”.

FIG. 88 shows the amino acid sequence (SEQ ID NO:250) derived from the coding sequence of SEQ ID NO:249 shown in FIG. 87.

FIG. 89 shows a nucleotide sequence (SEQ ID NO:254) of a native sequence PRO302 cDNA, wherein SEQ ID NO:254 is a clone designated herein as “DNA40370-1217”.

FIG. 90 shows the amino acid sequence (SEQ ID NO:255) derived from the coding sequence of SEQ ID NO:254 shown in FIG. 89.

FIG. 91 shows a nucleotide sequence (SEQ ID NO:256) of a native sequence PRO303 cDNA, wherein SEQ ID NO:256 is a clone designated herein as “DNA42551-1217”.

FIG. 92 shows the amino acid sequence (SEQ ID NO:257) derived from the coding sequence of SEQ ID NO:256 shown in FIG. 91.

FIG. 93 shows a nucleotide sequence (SEQ ID NO:258) of a native sequence PRO304 cDNA, wherein SEQ ID NO:258 is a clone designated herein as “DNA39520-1217”.

FIG. 94 shows the amino acid sequence (SEQ ID NO:259) derived from the coding sequence of SEQ ID NO:258 shown in FIG. 93.

FIG. 95 shows a nucleotide sequence (SEQ ID NO:260) of a native sequence PRO307 cDNA, wherein SEQ ID NO:260 is a clone designated herein as “DNA41225-1217”.

FIG. 96 shows the amino acid sequence (SEQ ID NO:261) derived from the coding sequence of SEQ ID NO:260 shown in FIG. 95.

FIG. 97 shows a nucleotide sequence (SEQ ID NO:262) of a native sequence PRO343 cDNA, wherein SEQ ID NO:262 is a clone designated herein as “DNA43318-1217”.

FIG. 98 shows the amino acid sequence (SEQ ID NO:263) derived from the coding sequence of SEQ ID NO:262 shown in FIG. 97.

FIG. 99 shows a nucleotide sequence (SEQ ID NO:284) of a native sequence PRO328 cDNA, wherein SEQ ID NO:284 is a clone designated herein as “DNA40587-1231”.

FIG. 100 shows the amino acid sequence (SEQ ID NO:285) derived from the coding sequence of SEQ ID NO:284 shown in FIG. 99.

FIG. 101 shows a nucleotide sequence (SEQ ID NO:289) of a native sequence PRO335 cDNA, wherein SEQ ID NO:289 is a clone designated herein as “DNA41388-1234”.

FIG. 102 shows the amino acid sequence (SEQ ID NO:290) derived from the coding sequence of SEQ ID NO:289 shown in FIG. 101.

FIG. 103 shows a nucleotide sequence (SEQ ID NO:291) of a native sequence PRO331 cDNA, wherein SEQ ID NO:291 is a clone designated herein as “DNA40981-1234”.

FIG. 104 shows the amino acid sequence (SEQ ID NO:292) derived from the coding sequence of SEQ ID NO:291 shown in FIG. 103.

FIG. 105 shows a nucleotide sequence (SEQ ID NO:293) of a native sequence PRO326 cDNA, wherein SEQ ID NO:293 is a clone designated herein as “DNA37140-1234”.

FIG. 106 shows the amino acid sequence (SEQ ID NO:294) derived from the coding sequence of SEQ ID NO:293 shown in FIG. 105.

FIG. 107 shows a nucleotide sequence (SEQ ID NO:309) of a native sequence PRO332 cDNA, wherein SEQ ID NO:309 is a clone designated herein as “DNA40982-1235”.

FIG. 108 shows the amino acid sequence (SEQ ID NO:310) derived from the coding sequence of SEQ ID NO:309 shown in FIG. 107.

FIG. 109 shows a nucleotide sequence (SEQ ID NO:314) of a native sequence PRO334 cDNA, wherein SEQ ID NO:314 is a clone designated herein as “DNA41379-1236”.

FIG. 110 shows the amino acid sequence (SEQ ID NO:315) derived from the coding sequence of SEQ ID NO:314 shown in FIG. 109.

FIG. 111 shows a nucleotide sequence (SEQ ID NO:319) of a native sequence PRO346 cDNA, wherein SEQ ID NO:319 is a clone designated herein as “DNA44167-1243”.

FIG. 112 shows the amino acid sequence (SEQ ID NO:320) derived from the coding sequence of SEQ ID NO:319 shown in FIG. 111.

FIG. 113 shows a nucleotide sequence (SEQ ID NO:324) of a native sequence PRO268 cDNA, wherein SEQ ID NO:324 is a clone designated herein as “cDNA39427-1179”.

FIG. 114 shows the amino acid sequence (SEQ ID NO:325) derived from the coding sequence of SEQ ID NO:324 shown in FIG. 113.

FIG. 115 shows a nucleotide sequence (SEQ ID NO:331) of a native sequence PRO330 cDNA, wherein SEQ ID NO:331 is a clone designated herein as “DNA40603-1232”.

FIG. 116 shows the amino acid sequence (SEQ ID NO:332) derived from the coding sequence of SEQ ID NO:331 shown in FIG. 115.

FIG. 117 shows a nucleotide sequence (SEQ ID NO:338) of a native sequence PRO339 cDNA, wherein SEQ ID NO:338 is a clone designated herein as “DNA43466-1225”.

FIG. 118 shows the amino acid sequence (SEQ ID NO:339) derived from the coding sequence of SEQ ID NO:338 shown in FIG. 117.

FIG. 119 shows a nucleotide sequence (SEQ ID NO:340) of a native sequence PRO310 cDNA, wherein SEQ ID NO:340 is a clone designated herein as “DNA43046-1225”.

FIG. 120 shows the amino acid sequence (SEQ ID NO:341) derived from the coding sequence of SEQ ID NO:340 shown in FIG. 119.

FIG. 121 shows a nucleotide sequence (SEQ ID NO:376) of a native sequence PRO244 cDNA, wherein SEQ ID NO:376 is a clone designated herein as “DNA35668-1171”.

FIG. 122 shows the amino acid sequence (SEQ ID NO:377) derived from the coding sequence of SEQ ID NO:376 shown in FIG. 121.

FIG. 123 shows a nucleotide sequence (SEQ ID NO:422) of a native sequence PRO1868 cDNA, wherein SEQ ID NO:422 is a clone designated herein as “DNA77624-2515”.

FIG. 124 shows the amino acid sequence (SEQ ID NO:423) derived from the coding sequence of SEQ ID NO:422 shown in FIG. 123.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

The terms “PRO polypeptide” and “PRO” as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein. The terms “PRO/number polypeptide” and “PRO/number” wherein the term “number” is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein). The PRO polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods.

A “native sequence PRO polypeptide” comprises a polypeptide having the same amino acid sequence as the corresponding PRO polypeptide derived from nature. Such native sequence PRO polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term “native sequence PRO polypeptide” specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. In various embodiments of the invention, the native sequence PRO polypeptides disclosed herein are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures. Start and stop codons are shown in bold font and underlined in the figures. However, while the PRO polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO polypeptides.

The PRO polypeptide “extracellular domain” or “ECD” refers to a form of the PRO polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO polypeptide ECD will have less than 1% of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains. It will be understood that any transmembrane domains identified for the PRO polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein. Optionally, therefore, an extracellular domain of a PRO polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are contemplated by the present invention.

The approximate location of the “signal peptides” of the various PRO polypeptides disclosed herein are shown in the present specification and/or the accompanying figures. It is noted, however, that the C-terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C-terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6 (1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)). Moreover, it is also recognized that, in some cases, cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species. These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.

“PRO polypeptide variant” means an active PRO polypeptide as defined above or below having at least about 80% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Such PRO polypeptide variants include, for instance, PRO polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO polypeptide variant will have at least about 80% amino acid sequence identity, preferably at least about 81% amino acid sequence identity, more preferably at least about 82% amino acid sequence identity, more preferably at least about 83% amino acid sequence identity, more preferably at least about 84% amino acid sequence identity, more preferably at least about 85% amino acid sequence identity, more preferably at least about 86% amino acid sequence identity, more preferably at least about 87% amino acid sequence identity, more preferably at least about 88% amino acid sequence identity, more preferably at least about 89% amino acid sequence identity, more preferably at least about 90% amino acid sequence identity, more preferably at least about 91% amino acid sequence identity, more preferably at least about 92% amino acid sequence identity, more preferably at least about 93% amino acid sequence identity, more preferably at least about 94% amino acid sequence identity, more preferably at least about 95% amino acid sequence identity, more preferably at least about 96% amino acid sequence identity, more preferably at least about 97% amino acid sequence identity, more preferably at least about 98% amino acid sequence identity and most preferably at least about 99% amino acid sequence identity with a full-length native sequence PRO polypeptide sequence as disclosed herein, a PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length PRO polypeptide sequence as disclosed herein. Ordinarily, PRO variant polypeptides are at least about 10 amino acids in length, often at least about 20 amino acids in length, more often at least about 30 amino acids in length, more often at least about 40 amino acids in length, more often at least about 50 amino acids in length, more often at least about 60 amino acids in length, more often at least about 70 amino acids in length, more often at least about 80 amino acids in length, more often at least about 90 amino acids in length, more often at least about 100 amino acids in length, more often at least about 150 amino acids in length, more often at least about 200 amino acids in length, more often at least about 300 amino acids in length, or more.

“Percent (%) amino acid sequence identity” with respect to the PRO polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. As examples of % amino acid sequence identity calculations using this method, Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated “Comparison Protein” to the amino acid sequence designated “PRO”, wherein “PRO” represents the amino acid sequence of a hypothetical PRO polypeptide of interest, “Comparison Protein” represents the amino acid sequence of a polypeptide against which the “PRO” polypeptide of interest is being compared, and “X, “Y” and “Z” each represent different hypothetical amino acid residues.

Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, % amino acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program (Altschul et al., Methods in Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=11, and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % amino acid sequence identity value is determined by dividing (a) the number of matching identical amino acid residues between the amino acid sequence of the PRO polypeptide of interest having a sequence derived from the native PRO polypeptide and the comparison amino acid sequence of interest (i.e., the sequence against which the PRO polypeptide of interest is being compared which may be a PRO variant polypeptide) as determined by WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest. For example, in the statement “a polypeptide comprising an the amino acid sequence A which has or having at least 80% amino acid sequence identity to the amino acid sequence B”, the amino acid sequence A is the comparison amino acid sequence of interest and the amino acid sequence B is the amino acid sequence of the PRO polypeptide of interest.

Percent amino acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et al., Nucleic Acids Res. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask=yes, strand=all, expected occurrences=10, minimum low complexity length=15/5, multi-pass e-value=0.01, constant for multi-pass=25, dropoff for final gapped alignment=25 and scoring matrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A.

“PRO variant polynucleotide” or “PRO variant nucleic acid sequence” means a nucleic acid molecule which encodes an active PRO polypeptide as defined below and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Ordinarily, a PRO variant polynucleotide will have at least about 80% nucleic acid sequence identity, more preferably at least about 81% nucleic acid sequence identity, more preferably at least about 82% nucleic acid sequence identity, more preferably at least about 83% nucleic acid sequence identity, more preferably at least about 84% nucleic acid sequence identity, more preferably at least about 85% nucleic acid sequence identity, more preferably at least about 86% nucleic acid sequence identity, more preferably at least about 87% nucleic acid sequence identity, more preferably at least about 88% nucleic acid sequence identity, more preferably at least about 89% nucleic acid sequence identity, more preferably at least about 90% nucleic acid sequence identity, more preferably at least about 91% nucleic acid sequence identity, more preferably at least about 92% nucleic acid sequence identity, more preferably at least about 93% nucleic acid sequence identity, more preferably at least about 94% nucleic acid sequence identity, more preferably at least about 95% nucleic acid sequence identity, more preferably at least about 96% nucleic acid sequence identity, more preferably at least about 97% nucleic acid sequence identity, more preferably at least about 98% nucleic acid sequence identity and yet more preferably at least about 99% nucleic acid sequence identity with a nucleic acid sequence encoding a full-length native sequence PRO polypeptide sequence as disclosed herein, a full-length native sequence PRO polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO polypeptide, with or without the signal sequence, as disclosed herein or any other fragment of a full-length PRO polypeptide sequence as disclosed herein. Variants do not encompass the native nucleotide sequence.

Ordinarily, PRO variant polynucleotides are at least about 30 nucleotides in length, often at least about 60 nucleotides in length, more often at least about 90 nucleotides in length, more often at least about 120 nucleotides in length, more often at least about 150 nucleotides in length, more often at least about 180 nucleotides in length, more often at least about 210 nucleotides in length, more often at least about 240 nucleotides in length, more often at least about 270 nucleotides in length, more often at least about 300 nucleotides in length, more often at least about 450 nucleotides in length, more often at least about 600 nucleotides in length, more often at least about 900 nucleotides in length, or more.

“Percent (%) nucleic acid sequence identity” with respect to PRO-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. For purposes herein, however, % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In situations where ALIGN-2 is employed for nucleic acid sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. As examples of % nucleic acid sequence identity calculations, Tables 4 and 5, demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated “Comparison DNA” to the nucleic acid sequence designated “PRO-DNA”, wherein “PRO-DNA” represents a hypothetical PRO-encoding nucleic acid sequence of interest, “Comparison DNA” represents the nucleotide sequence of a nucleic acid molecule against which the “PRO-DNA” nucleic acid molecule of interest is being compared, and “N”, “L” and “V” each represent different hypothetical nucleotides.

Unless specifically stated otherwise, all % nucleic acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program. However, % nucleic acid sequence identity values may also be obtained as described below by using the WU-BLAST-2 computer program (Altschul et al., Methods in Enzymology 266:460-480 (1996)). Most of the WU-BLAST-2 search parameters are set to the default values. Those not set to default values, i.e., the adjustable parameters, are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=11, and scoring matrix=BLOSUM62. When WU-BLAST-2 is employed, a % nucleic acid sequence identity value is determined by dividing (a) the number of matching identical nucleotides between the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest having a sequence derived from the native sequence PRO polypeptide-encoding nucleic acid and the comparison nucleic acid molecule of interest (i.e., the sequence against which the PRO polypeptide-encoding nucleic acid molecule of interest is being compared which may be a variant PRO polynucleotide) as determined by WU-BLAST-2 by (b) the total number of nucleotides of the PRO polypeptide-encoding nucleic acid molecule of interest. For example, in the statement “an isolated nucleic acid molecule comprising a nucleic acid sequence A which has or having at least 80% nucleic acid sequence identity to the nucleic acid sequence B”, the nucleic acid sequence A is the comparison nucleic acid molecule of interest and the nucleic acid sequence B is the nucleic acid sequence of the PRO polypeptide-encoding nucleic acid molecule of interest.

Percent nucleic acid sequence identity may also be determined using the sequence comparison program NCBI-BLAST2 (Altschul et at., Nucleic Acids Res. 25:3389-3402 (1997)). NCBI-BLAST2 uses several search parameters, wherein all of those search parameters are set to default values including, for example, unmask=yes, strand=all, expected occurrences=10, minimum low complexity length=15/5, multi-pass e-value=0.01, constant for multi-pass=25, dropoff for final gapped alignment=25 and scoring matrix=BLOSUM62.

In situations where NCBI-BLAST2 is employed for sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by the sequence alignment program NCBI-BLAST2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C.

In other embodiments, PRO variant polynucleotides are nucleic acid molecules that encode an active PRO polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO polypeptide as disclosed herein. PRO variant polypeptides may be those that are encoded by a PRO variant polynucleotide.

The term “positives”, in the context of sequence comparison performed as described above, includes residues in the sequences compared that are not identical but have similar properties (e.g. as a result of conservative substitutions, see Table 6 below). For purposes herein, the % value of positives is determined by dividing (a) the number of amino acid residues scoring a positive value between the PRO polypeptide amino acid sequence of interest having a sequence derived from the native PRO polypeptide sequence and the comparison amino acid sequence of interest (i.e., the amino acid sequence against which the PRO polypeptide sequence is being compared) as determined in the BLOSUM62 matrix of WU-BLAST-2 by (b) the total number of amino acid residues of the PRO polypeptide of interest.

Unless specifically stated otherwise, the % value of positives is calculated as described in the immediately preceding paragraph. However, in the context of the amino acid sequence identity comparisons performed as described for ALIGN-2 and NCBI-BLAST-2 above, includes amino acid residues in the sequences compared that are not only identical, but also those that have similar properties. Amino acid residues that score a positive value to an amino acid residue of interest are those that are either identical to the amino acid residue of interest or are a preferred substitution (as defined in Table 6 below) of the amino acid residue of interest.

For amino acid sequence comparisons using ALIGN-2 or NCBI-BLAST2, the % value of positives of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % positives to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scoring a positive value as defined above by the sequence alignment program ALIGN-2 or NCBI-BLAST2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % positives of A to B will not equal the % positives of B to A.

“Isolated, ” when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the PRO polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

An “isolated” PRO polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the form or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.

The term “control sequences” refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

The term “antibody” is used in the broadest sense and specifically covers, for example, single anti-PRO monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO antibody compositions with polyepitopic specificity, single chain anti-PRO antibodies, and fragments of anti-PRO antibodies (see below). The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts.

“Stringency” of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995).

“Stringent conditions” or “high stringency conditions”, as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3) employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5×Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS, and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC (sodium chloride/sodium citrate) and 50% formamide at 55° C., followed by a high-stringency wash consisting of 0.1×SSC containing EDTA at 55° C.

“Moderately stringent conditions” may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and % SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37° C. in a solution comprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1×SSC at about 37-50° C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

The term “epitope tagged” when used herein refers to a chimeric polypeptide comprising a PRO polypeptide fused to a “tag polypeptide”. The tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused. The tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).

As used herein, the term “immunoadhesin” designates antibody-like molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is “heterologous”), and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The inmmunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.

“Active” or “activity” for the purposes herein refers to form(s) of a PRO polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO, wherein “biological” activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring PRO other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO and an “immunological” activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO.

The term “antagonist” is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO polypeptide disclosed herein. In a similar manner, the term “agonist” is used in the broadest sense and includes any molecule that mimics a biological activity of a native PRO polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a PRO polypeptide may comprise contacting a PRO polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO polypeptide.

“Treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whom the disorder is to be prevented.

“Chronic” administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. “Intermittent” administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.

“Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human.

Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

“Carriers” as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

“Antibody fragments” comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, and Fv fragments; diabodies; linear antibodies (Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment yields an F(ab′)₂ fragment that has two antigen-combining sites and is still capable of cross-linking antigen.

“Fv” is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V_(H)-V_(L) dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments differ from Fab′ fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region. Fab′-SH is the designation herein for Fab′ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab′)₂ antibody fragments originally were produced as pairs of Fab′ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

The “light chains” of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.

Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

“Single-chain Fv” or “sFv” antibody fragments comprise the V_(H) and V_(L) domains of antibody, wherein these domains are present in a single polypeptide chain. Preferably, the Fv polypeptide further comprises a polypeptide linker between the V_(H)and V_(L) domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (V_(H)) connected to a light-chain variable domain (V_(L)) in the same polypeptide chain (V_(H)-V_(L)). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. U.S.A., 90:6444-6448 (1993).

An “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

The word “label” when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a “labeled” antibody. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.

By “solid phase” is meant a non-aqueous matrix to which the antibody of the present invention can adhere. Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. In certain embodiments, depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149.

A “liposome” is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a PRO polypeptide or antibody thereto) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

A “small molecule” is defined herein to have a molecular weight below about 500 Daltons.

“PRO317-associated disorder” refers to a pathological condition or disease wherein PRO317 is over- or underexpressed. Such disorders include diseases of the female genital tract or of the endometrium of a mammal, including hyperplasia, endometritis, endometriosis, wherein the patient is at risk for infertility due to endometrial factor, endometrioma, and endometrial cancer, especially those diseases involving abnormal bleeding such as a gynecological disease. They also include diseases involving angiogenesis, wherein the angiogenesis results in a pathological condition, such as cancer involving solid tumors (the therapy for the disorder would result in decreased vascularization and a decline in growth and metastasis of a variety of tumors). Alternatively, the angiogenesis may be beneficial, such as for ischemia, especially coronary ischemia. Hence, these disorders include those found in patients whose hearts are functioning but who have a blocked blood supply due to atherosclerotic coronary artery disease, and those with a functioning but underperfused heart, including patients with coronary arterial disease who are not optimal candidates for angioplasty and coronary artery by-pass surgery. The disorders also include diseases involving the kidney or originating from the kidney tissue, such as polycystic kidney disease and chronic and acute renal failure.

TABLE 1 /*  *  * C-C increased from 12 to 15  * Z is average of EQ  * B is average of ND  * match with stop is _M; stop-stop = 0; J (joker) match = 0  */ #define _M −8 /* value of a match with a stop */ int _day[26][26] = { /*  A B C D E F G H I J K L M N O P Q R S T U V W X Y Z */ /* A */ { 2, 0, −2, 0, 0, −4, 1, −1, −1, 0, −1, −2, −1, 0, _M, 1, 0, −2, 1, 1, 0, 0, −6, 0, −3, 0}, /* B */ { 0, 3, −4, 3, 2, −5, 0, 1, −2, 0, 0, −3, −2, 2, _M, −1, 1, 0, 0, 0, 0, −2, −5, 0, −3, 1}, /* C */ {−2, −4, 15, −5, −5, −4, −3, −3, −2, 0, −5, −6, −5, −4, _M, −3, −5, −4, 0, −2, 0, −2, −8, 0, 0, −5}, /* D */ {0, 3, −5, 4, 3, −6, 1, 1, −2, 0, 0, −4, −3, 2, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 2}, /* E */ {0, 2, −5, 3, 4, −5, 0, 1, −2, 0, 0, −3, −2, 1, _M, −1, 2, −1, 0, 0, 0, −2, −7, 0, −4, 3}, /* F */ {−4, −5, −4, −6, −5, 9, −5, −2, 1, 0, −5, 2, 0, −4, _M, −5, −5, −4, −3, −3, 0, −1, 0, 0, 7, −5}, /* G */ { 1, 0, −3, 1, 0, −5, 5, −2, −3, 0, −2, −4, −3, 0, _M, −1, −1, −3, 1, 0, 0, −1, −7, 0, −5, 0}, /* H */ {−1, 1, −3, 1, 1, −2, −2, 6, −2, 0, 0, −2, −2, 2, _M, 0, 3, 2, −1, −1, 0, −2, −3, 0, 0, 2}, /* I */ {−1, −2, −2, −2, −2, 1, −3, −2, 5, 0, −2, 2, 2, −2, _M, −2, −2, −2, −1, 0, 0, 4, −5, 0, −1, −2}, /* J */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* K */ {−1, 0, −5, 0, 0, −5, −2, 0, −2, 0, 5, −3, 0, 1, _M, −1, 1, 3, 0, 0, 0, −2, −3, 0, −4, 0}, /* L */ {−2, −3, −6, −4, −3, 2, −4, −2, 2, 0, −3, 6, 4, −3, _M, −3, −2, −3, −3 , −1, 0, 2, −2, 0, −1, −2} /* M */ {−1, −2, −5, −3, −2, 0, −3, −2, 2, 0, 0, 4, 6, −2, _M, −2, −1, 0, −2, −1, 0, 2, −4, 0, −2, −1}, /* N */ {0, 2, −4, 2, 1, −4, 0, 2, −2, 0, 1, −3, −2, 2, _M, −1, 1, 0, 1, 0, 0, −2, −4, 0, −2, 1}, /* O */ {_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M, 0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,}, /* P */ {1, −1, −3, −1, −1, −5, −1, 0, −2, 0, −1, −3, −2, −1,_M, 6, 0, 0, 1, 0, 0, −1, −6, 0, −5, 0}, /* Q */ {0, 1, −5, 2, 2, −5, −1, 3, −2, 0, 1, −2, −1, 1, _M, 0, 4, 1, −1, −1, 0, −2, −5, 0, −4, 3}, /* R */ {−2, 0, −4, −1, −1, −4, −3, 2, −2, 0, 3, −3, 0, 0, _M, 0, 1, 6, 0, −1, 0, −2, 2, 0, −4, 0}, /* S */ { 1, 0, 0, 0, 0, −3, 1, −1, −1, 0, 0, −3, −2, 1, _M, 1, −1, 0, 2, 1, 0, −1, −2, 0, −3, 0}, /* T */ { 1, 0, −2, 0, 0, −3, 0, −1, 0, 0, 0, −1, −1, 0, _M, 0, −1, −1, 1, 3, 0, 0, −5, 0, −3, 0}, /* U */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ {0, −2, −2, −2, −2, −1, −1, −2, 4, 0, −2, 2, 2, −2,_M, −1, −2, −2, −1, 0, 0, 4, −6, 0, −2, −2}, /* W */ {−6, −5, −8, −7, −7, 0, −7, −3, −5, 0, −3, −2, −4, −4,_M, −6, −5, 2, −2, −5, 0, −6, 17, 0, 0, −6}, /* X */ {0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, _M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* Y */ {−3, −3, 0, −4, −4, 7, −5, 0, −1, 0, −4, −1, −2, −2, _M, −5, −4, −4, −3, −3, 0, −2, 0, 0, 10, −4}, /* Z */ { 0, 1, −5, 2, 3, −5, 0, 2, −2, 0, 0, −2, −1, 1,_M, 0, 3, 0, 0, 0, 0, −2, −6, 0, −4, 4}, }; /*  */ #include <stdio.h> #include <ctype.h> #define MAXJMP  16 /* max jumps in a diag */ #define MAXGAP  24 /* don't continue to penalize gaps larger than this */ #define JMPS 1024 /* max jmps in an path */ #define MX   4 /* save if there's at least MX-1 bases since last jmp */ #define DMAT   3 /* value of matching bases */ #define DMIS   0 /* penalty for mismatched bases */ #define DINS0   8 /* penalty for a gap */ #define DINS1   1 /* penalty per base */ #define PINS0   8 /* penalty for a gap */ #define PINS1   4 /* penalty per residue */ struct jmp { short n[MAXJMP]; /* size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /* base no. of jmp in seq x */ /* limits seq to 2{circumflex over ( )}16 −1 */ }; struct diag { int score; /* score at last jmp */ long offset; /* offset of prev block */ short ijmp; /* current jmp index */ struct jmp jp; /* list of jmps */ }; struct path { int spc; /* number of leading spaces */ short n[JMPS]; /* size of jmp (gap) */ int x[JMPS]; /* loc of jmp (last elem before gap) */ }; char *ofile; /* output file name */ char *namex[2]; /* seq names: getseqs( ) */ char *prog; /* prog name for err msgs */ char *seqx[2];   /* seqs: getseqs( ) */ int dmax; /* best diag: nw( ) */ int dmax0; /* final diag */ int dna; /* set if dna: main( ) */ int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /* total gaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy; /* total size of gaps */ int smax; /* max score: nw( ) */ int *xbm; /* bitmap for matching */ long offset; /* current offset in jmp file */ struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds path for seqs */ char *calloc( ), *malloc( ), *index( ), *strcpy( ); char *getseq( ), *g_calloc( ); /* Needleman-Wunsch alignment program  *  * usage: progs file1 file2  * where file1 and file2 are two dna or two protein sequences.  * The sequences can be in upper- or lower-case an may contain ambiguity  * Any lines beginning with ‘;’, ‘>’ or ‘<’ are ignored  * Max file length is 65535 (limited by unsigned short x in the jmp struct)  * A sequence with ⅓ or more of its elements ACGTU is assumed to be DNA  * Output is in the file “align.out”  *  * The program may create a tmp file in /tmp to hold info about traceback.  * Original version developed under BSD 4.3 on a vax 8650  */ #include “nw.h” #include “day.h” static _dbval[26] = { 1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static _pbval[26] = { 1, 2|(1< <(‘D’-‘A’))|(1< <(‘N’-‘A’)), 4, 8, 16, 32, 64, 128, 256, 0×FFFFFFF, 1< <10, 1< <11, 1< <12, 1< <13, 1< <14, 1< <15, 1< <16, 1< <17, 1< <18, 1< <19, 1< <20, 1< <21, 1< <22, 1< <23, 1< <24, 1< <25|(1< <(‘E’-‘A’))|(1< <(‘Q’-‘A’)) }; main(ac, av) main int ac; char *av[]; { prog = av[0]; if(ac != 3) { fprintf(stderr, “usage: %s file1 file2\n”, prog); fprintf(stderr, “where file1 and file2 are two dna or two protein sequences.\n”); fprintf(stderr, “The sequences can be in upper- or lower-case\n”); fprintf(stderr, “Any lines beginning with ‘;’ or ‘<’ are ignored\n”); fprintf(stderr, “Output is in the file \“align.out\”\n”); exit(1); } namex[0] = av[1]; namex[1] = av[2]; seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1); xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ ofile = “align.out”; /* output file */ nw( ); /* fill in the matrix, get the possible jmps */ readjmps( ); /* get the actual jmps */ print( ); /* print stats, alignment */ cleanup(0); /* unlink any tmp files */ } /* do the alignment, return best score: main( )  * dna: values in Fitch and Smith, PNAS, 80, 1382-1386, 1983  * pro: PAM 250 values  * When scores are equal, we prefer mismatches to any gap, prefer  * a new gap to extending an ongoing gap, and prefer a gap in seqx  * to a gap in seq y.  */ nw( ) nw { char *px, *py;   /* seqs and ptrs */ int *ndely, *dely; /* keep track of dely */ int ndelx, delx; /* keep track of delx */ int *tmp; /* for swapping row0, row1 */ int mis; /* score for each type */ int ins0, ins1; /* insertion penalties */ register id; /* diagonal index */ register ij; /* jmp index */ register *col0, *col1; /* score for curr, last row */ register xx, yy; /* index into seqs */ dx = (struct diag *)g_calloc(“to get diags”, len0+len1+1, sizeof(struct diag)); ndely = (int *)g_calloc(“to get ndely”, len1+1, sizeof(int)); dely = (int *)g_calloc(“to get dely”, len1+1, sizeof(int)); col0 = (int *)g_calloc(“to get col0”, len1+1, sizeof(int)); col1 = (int *)g_calloc(“to get col1”, len1+1, sizeof(int)); ins0 = (dna)? DINS0 : PINS0; ins1 = (dna)? DINS1 : PlNS1; smax = −10000; if (endgaps) { for (col0[0] = dely[0] = −ins0, yy = 1; yy <= len1; yy++) { col0[yy] = dely[yy] = col0[yy−1] − ins1; ndely[yy] = yy; } col0[0] = 0; /* Waterman Bull Math Biol 84 */ } else for (yy= 1; yy <= len1; yy++) dely[yy] = −ins0; /* fill in match matrix  */ for (px = seqx[0], xx = 1; xx <= len0; px++, xx++) { /* initialize first entry in col  */ if (endgaps) { if (xx == 1) col1[0] = delx = −(ins0+ins1); else col1[0] = delx = col0[0]−ins1; ndelx = xx; } else { col1[0] = 0; delx = −ins0; ndelx = 0; } ...nw for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) { mis = col0[yy−1]; if (dna) mis + = (xbm[*px−‘A’]&xbm[*py−‘A’])? DMAT : DMIS; else mis + = _day[*px−‘A’][*py−‘A’]; /* update penalty for del in x seq;  * favor new del over ongong del  * ignore MAXGAP if weighting endgaps  */ if (endgaps || ndely[yy] < MAXGAP) { if (col0[yy] − ins0 >= dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } else { dely[yy] −= ins1; ndely[yy]++; } } else { if (col0[yy] − (ins0+ins1) >= dely[yy]) { dely[yy] = col0[yy] − (ins0+ins1); ndely[yy] = 1; } else ndely[yy]++; } /* update penalty for del in y seq;  * favor new del over ongong del  */ if (endgaps || ndelx < MAXGAP) { if(col1[yy−1] − ins0 >= delx) { delx = col1[yy−1] − (ins0+ins1); ndelx = 1; } else { delx −= ins1; ndelx++; } } else { if (col1[yy−1] − (ins0+ins1) > = delx) { delx = col1[yy−1] − (ins0+ins1); ndelx = 1; } else ndelx+ +; } /* pick the maximum score; we're favoring  * mis over any del and delx over dely  */ . . .nw id = xx − yy + len1 − 1; if (mis >= delx && mis >= dely[yy]) col1[yy] = mis; else if (delx > = dely[yy]) { col1[yy] = delx; ij = dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndelx > = MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp+ +; if (++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset += sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx; dx[id].score = delx; } else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndely[yy] > = MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp++; if (++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset += sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] =−ndely[yy]; dx[id].jp.x[ij] = xx; dx[id].score = dely[yy]; } if (xx == len0 && yy < len1) { /* last col  */ if (endgaps) col1[yy] −= ins0+ins1*(len1−yy); if(col1[yy] > smax) { smax = col1[yy]; dmax = id; } } } if (endgaps && xx < len0) col1[yy−1] −= ins0+ins1*(len0−xx); if (col1[yy−1] > smax) { smax = col1[yy−1]; dmax = id; } tmp = col0; col0 = col1; col1 = tmp; } (void) free((char *)ndely); (void) free((char *)dely); (void) free((char *)col0); (void) free((char *)col1); } /*  *  * print( ) -- only routine visible outside this module  *  * static:  * getmat( ) -- trace back best path, count matches: print( )  * pr_align( ) -- print alignment of described in array p[]: print( )  * dumpblock( ) -- dump a block of lines with numbers, stars: pr_align( )  * nums( ) -- put out a number line: dumpblock( )  * putline( ) -- put out a line (name, [num], seq, [num]): dumpblock( )  * stars( ) - -put a line of stars: dumpblock( )  * stripname( ) -- strip any path and prefix from a seqname  */ #include “nw.h” #define SPC  3 #define P_LINE 256 /* maximum output line */ #define P_SPC  3 /* space between name or num and seq */ extern _day[26][26]; int olen; /* set output line length */ FILE *fx; /* output file */ print( ) print { int lx, ly, firstgap, lastgap;  /* overlap */ if ((fx = fopen(ofile, “w”)) == 0) { fprintf(stderr, “ %s: can't write %s\n”, prog, ofile); cleanup(1); } fprintf(fx, “<first sequence: %s (length = %d)\n”, namex[0], len0); fprintf(fx, “<second sequence: %s (length = %d)\n”, namex[1], len1); olen = 60; lx = len0; ly = len1; firstgap = lastgap = 0; if (dmax < len1 − 1) { /* leading gap in x */ pp[0].spc = firstgap = len1 − dmax − 1; ly −= pp[0].spc; } else if (dmax > len1 − 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax − (len1 − 1); lx −= pp[1].spc; } if (dmax0 < len0 − 1) { /* trailing gap in x */ lastgap = len0 − dmax0 −1; lx −= lastgap; } else if (dmax0 > len0 − 1) { /* trailing gap in y */ lastgap = dmax0 − (len0 − 1); ly −= lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align( ); } /*  * trace back the best path, count matches  */ static getmat(lx, ly, firstgap, lastgap) getmat int lx, ly; /* “core” (minus endgaps) */ int firstgap, lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1; char outx[32]; double pct; register n0, n1; register char *p0, *p1; /* get total matches, score  */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] + pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 = pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1++; n1++; siz0−−; } else if (siz1) { p0+ +; n0+ +; siz1−−; } else { if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) nm+ +; if (n0++ == pp[0].x[i0]) siz0 = pp[0].n[i0++]; if (nl++ == pp[1].x[i1]) siz1 = pp[1].n[il++]; p0+ +; p1++; } } /* pct homology:  * if penalizing endgaps, base is the shorter seq  * else, knock off overhangs and take shorter core  */ if (endgaps) lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx : ly; pct = 100.*(double)nm/(double)lx; fprintf(fx, “\n”); fprintf(fx, “< %d match%s in an overlap of %d: %.2f percent similarity\n”, nm, (nm == 1)? “” : “es”, lx, pct); fprintf(fx, “<gaps in first sequence: %d”, gapx); ...getmat if (gapx) { (void) sprintf(outx, “ (%d %s%s)”, ngapx, (dna)? “base”: “residue”, (ngapx == 1)? “”:“s”); fprintf(fx, “% s”, outx); fprintf(fx, “, gaps in second sequence: %d”, gapy); if (gapy) { (void) sprintf(outx, “(%d %s%s)”, ngapy, (dna)? “base”:“residue”, (ngapy == 1)? “”:“s”); fprintf(fx, “%s”, outx); } if (dna) fprintf(fx, “\n<score: %d (match = %d, mismatch = %d, gap penalty = %d + %d per base)\n”, smax, DMAT, DMIS, DINS0, DINS1); else fprintf(fx, “\n< score: %d (Dayhoff PAM 250 matrix, gap penalty = %d + %d per residue)\n”, smax, PINS0, PINS1); if (endgaps) fprintf(fx, “<endgaps penalized. left endgap: %d %s%s, right endgap: %d %s%s\n”, firstgap, (dna)? “base” : “residue”, (firstgap == 1)? “” : “s”, lastgap, (dna)? “base” : “residue”, (lastgap == 1)? “” : “s”); else fprintf(fx, “<endgaps not penalized\n”); } static nm; /* matches in core -- for checking */ static lmax; /* lengths of stripped file names */ static ij[2]; /* jmp index for a path */ static nc[2]; /* number at start of current line */ static ni[2]; /* current elem number -- for gapping */ static siz[2]; static char *ps[2]; /* ptr to current element */ static char *po[2]; /* ptr to next output char slot */ static char out[2][P_LINE]; /* output line */ static char star[P_LINE]; /* set by stars( ) */ /*  * print alignment of described in struct path pp[]  */ static pr_align( ) pr_align { int nn; /* char count */ int more; register i; for (i = 0, lmax = 0; i < 2++) { nn = stripname(namex[i]); if (nn > lmax) lmax = nn; nc[i] = 1; ni[i] = 1; siz[i] = ij[i] = 0; ps[i] = seqx[i]; po[i] = out[i]; } for (nn = nm = 0, more = 1; more;) { ...pr_align for (i = more = 0; i < 2; i++) { /*  * do we have more of this sequence?  */ if (!*ps[i]) continue; more++; if (pp[i].spc) { /* leading space */ *po[i]++ = ‘ ’; pp[i].spc−−; } else if (siz[i]) { /* in a gap */ *po[i]++ = ‘−’; siz[i]−−; } else { /* we're putting a seq element */ *po[i] = *ps[i]; if (islower(*ps[i])) *ps[i] = toupper(*ps[i]); po[i]++; ps[i]++; /*  * are we at next gap for this seq?  */ if (ni[i] == pp[i].x[ij[i]]) { /*  * we need to merge all gaps  * at this location  */ siz[i] == pp[i].n[ij[i]++]; while (ni[i] == pp[i].x[ij[i]]) siz[i] += pp[i].n[ij[i]++]; } ni[i]++; } } if (++nn == olen || !more && nn) { dumpblock( ); for (i = 0; i < 2; i++) po[i] = out[i]; nn = 0; } } } /*  * dump a block of lines, including numbers, stars: pr_align( )  */ static dumpblock( ) dumpblock { register i; for(i = 0; i < 2; i++) *po[i]−− = ‘\0’; ...dumpblock (void) putc(‘\n’, fx); for (i = 0; i < 2; i++) { if (*out[i] && (*out[i] != ‘ ’ || *(po[i]) != ‘ ’)) { if (i == 0) nums(i); if (i == 0 && *out[1]) stars( ); putline(i); if (i == 0 && *out[1]) fprintf(fx, star); if (i == 1) nums(i); } } } * put out a number line: dumpblock( )  */ static nums(ix) nums int  ix; /* index in out[] holding seq line */ { char nline[P_LINE]; register i, j; register char *pn, *px, *py; for(pn = nline, i = 0; i < lmax+P_SPC; i++, pn++) *pn = ‘ ’; for (i = nc[ix], py = out[ix]; *py; py++, pn++) { if (*py == ‘ ’ || *py == ‘−’); *pn = ‘ ’; else { if (i%10 == 0 || (i == 1 && nc[ix] != 1)) { j = (i < 0)? −i : i; for (px = pn; j; j/= 10, px−−) *px = j%10 + ‘0’; if (i < 0) *px = ‘−’; } else *pn = ‘ ’; i+ +; } } *pn = ‘\0’; nc[ix] = i; for (pn = nline; *pn; pn+ +) (void) putc(*pn, fx); (void) putc(‘\n’, fx); } /*  * put out a line (name, [num], seq. [num]): dumpblock( )  */ static putline(ix) putline int   ix; { ...putline int i; register char *px; for (px = namex[ix], i = 0; *px && *px != ‘:’; px++, i++) (void) putc(*px, fx); for (;i < lmax+P_SPC; i++) (void) putc(‘ ’, fx); /* these count from 1:  * ni[] is current element (from 1)  * nc[] is number at start of current line  */ for (px = out[ix]; *px; px+ +) (void) putc(*px&0x7F, fx); (void) putc(‘\n’, fx); } /*  * put a line of stars (seqs always in out[0], out[1]): dumpblock( )  */ static stars( ) stars { int i; register char *p0, *p1, cx, *px; if (!*out[0] || (*out[0] == ‘ ’ && *(p0[0]) == ‘ ’) || !*out[1] || (*out[1] == ‘ ’ && *(po[1]) == ‘ ’)) return; px = star; for (i = lmax+P_ SPC; i; i−−) *px++ = ‘ ’; for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0++, p1++) { if (isalpha(*p0) && isalpha(*p1)) { if (xbm[*p0−‘A’]&xbm[*p1−‘A’]) { cx = ‘*’; nm+ +; } else if (!dna && _day[*p0− ‘A’][*p1−‘A’] > 0) cx = ‘.’; else cx = ‘ ’; } else cx = ‘ ’; *px++ = cx; } *px++ = ‘\n’; *px = ‘\0’; } /*  * strip path or prefix from pn, return len: pr_align( )  */ static stripname(pn) stripname char *pn; /* file name (may be path) */ { register char *px, *py; py = 0; for (px = pn; *px; px++) if (*px == ‘/’) py = px + 1; if (py) (void) strcpy(pn, py); return(strlen(pn)); } /*  * cleanup( ) -- cleanup any tmp file  * getseq( ) -- read in seq, set dna, len, maxlen  * g_calloc( ) -- calloc( ) with error checkin  * readjmps( ) -- get the good jmps, from tmp file if necessary  * writejmps( ) -- write a filled array of jmps to a tmp file: nw( )  */ #include “nw.h” #include <sys/file.h> char *jname = “/tmp/homgXXXXXX”; /* tmp file for jmps */ FILE *fj; int cleanup( ); /* cleanup tmp file */ long lseek( ); /*  * remove any tmp file if we blow  */ cleanup(i) cleanup int i; { if (fj) (void) unlink(jname); exit(i); } /*  * read, return ptr to seq, set dna, len, maxlen  * skip lines starting with ‘;’, ‘<’, or ‘>’  * seq in upper or lower case  */ char * getseq(file, len) getseq char *file; /* file name */ int *len; /* seq len */ { char line[1024], *pseq; register char *px, *py; int natgc, tlen; FILE *fp; if ((fp = fopen(file, “r”)) == 0) { fprintf(stderr, “%s: can't read %s\n”, prog, file); exit(1); } tlen = natgc = 0; while (fgets(line, 1024, fp)) { if (*line == ‘;’ || *line == ‘<’ || *line == ‘>’) continue; for (px = line; *px != ‘\n’; px+ +) if (isupper(*px) || islower(*px)) tlen++; } if ((pseq = malloc((unsigned)(tlen+ 6))) == 0) { fprintf(stderr, “%s: malloc( ) failed to get %d bytes for %s\n”, prog, tlen+6, file); exit(1); } pseq[0] = pseq[1] = pseq[2] = pseq[3] = ‘\0’; ...getseq py = pseq + 4; *len = tlen; rewind(fp); while (fgets(line, 1024, fp)) { if (*line == ‘;’ || *line == ‘<’ || *line == ‘>’) continue; for (px = line; *px != ‘\n’; px++) { if (isupper(*px)) *py++ = *px; else if (islower(*px)) *py+ + = toupper(*px); if (index(“ATGCU” , *(py−1))) natgc+ +; } } *py++ = ‘\0’; *py = ‘\0’; (void) fclose(fp); dna = natgc > (tlen/3); return(pseq+4); } char * g_calloc(msg, nx, sz) g_calloc char *msg; /* program, calling routine */ int nx, sz; /* number and size of elements */ { char *px, *calloc( ); if ((px = calloc((unsigned)nx, (unsigned)sz)) == 0) { if (*msg) { fprintf(stderr, “%s: g_calloc( ) failed %s (n= %d, sz= %d)\n”, prog, msg, nx, sz); exit(1); } } return(px); } /*  * get final jmps from dx[] or tmp file, set pp[], reset dmax: main( )  */ readjmps( ) readjmps { int fd = −1; int siz, i0, i1; register i, j, xx; if (fj) { (void) fclose(fj); if ((fd = open(jname, O_RDONLY, 0)) < 0) { fprintf(stderr, “%s: can't open( ) %s\n”, prog, jname); cleanup(1); } } for (i = i0 = i1 = 0, dmax0 = dmax, xx = len0; ;i++) { while (1) { for (j = dx[dmax].ijmp; j >= 0 && dx[dmax].jp.x[j] >= xx; j−−) ; ...readjmps if (j < 0 && dx[dmax].offset && fj) { (void) lseek(fd, dx[dmax].offset, 0); (void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); (void) read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset)); dx[dmax].ijmp = MAXJMP−1; } else break; } if (i > = JMPS) { fprintf(stderr, “%s: too many gaps in alignment\n”, prog); cleanup(1); } if (j >= 0) { siz = dx[dmax].jp.n[j]; xx = dx[dmax].jp.x[j]; dmax += siz; if (siz < 0) { /* gap in second seq */ pp[1].n[il] = −siz; xx += siz; /* id = xx − yy + len1 − 1  */ pp[1].x[il] = xx − dmax + len1 − 1; gapy+ +; ngapy −= siz; /* ignore MAXGAP when doing endgaps */ siz = (−siz < MAXGAP || endgaps)? −siz : MAXGAP; il++; } else if (siz > 0) { /* gap in first seq */ pp[0] .n[i0] = siz; pp[0] .x[i0] = xx; gapx+ +; ngapx += siz; /* ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP || endgaps)? siz : MAXGAP; i0+ +; } } else break; } /* reverse the order of jmps  */ for (j = 0, i0−−; j < i0; j++, i0−−) { i = pp[0].n[j]; pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] = i; i = pp[0].x[j]; pp[0].x[j] = pp[0].x[i0]; pp[0].x[i0] = i; } for (j = 0, i1−−; j < i1; j++, i1−−) { i = pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = i; i = pp[1].x[j]; pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = i; } if (fd > = 0) (void) close(fd); if (fj) { (void) unlink(jname); fj = 0; offset = 0; } } /*  * write a filled jmp struct offset of the prev one (if any): nw( )  */ writejmps(ix) writejmps int ix; { char *mktemp( ); if (!fj) { if (mktemp(jname) < 0) { fprintf(stderr, “%s: can't mktemp( ) %s\n”, prog, jname); cleanup(1); } if ((fj = fopen(jname, “w”)) == 0) { fprintf(stderr, “%s: can't write %s\n”, prog, jname); exit(1); } } (void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void) fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) Comparison XXXXXYYYYYYY (Length = 12 amino acids) Protein % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO polypeptide) = 5 divided by 15 = 33.3%

TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) Comparison XXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO polypeptide) = 5 divided by 10 = 50%

TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA % nucleic acid sequence identity = (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) = 6 divided by 14 = 42.9%

TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison DNA NNNNLLLVV (Length = 9 nucleotides) % nucleic acid sequence identity = (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) = 4 divided by 12 = 33.3%

II. Compositions and Methods of the Invention

A. Full-Length PRO Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO polypeptides. In particular, cDNAs encoding various PRO polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed. However, for sake of simplicity, in the present specification the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as “PRO/number”, regardless of their origin or mode of preparation.

As disclosed in the Examples below, various cDNA clones have been deposited with the ATCC. The actual nucleotide sequences of those clones can readily be determined by the skilled artisan by sequencing of the deposited clone using routine methods in, the art. The predicted amino acid sequence can be determined from the nucleotide sequence using routine skill. For the PRO polypeptides and encoding nucleic acids described herein, Applicants have identified what is believed to be the reading frame best identifiable with the sequence information available at the time.

1. Full-length PRO211 and PRO217 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO211 and PRO217. In particular, Applicants have identified and isolated cDNA encoding PRO211 and PRO217 polypeptides, as disclosed in further detail in the Examples below. Using BLAST (FastA format) sequence alignment computer programs, Applicants found that cDNA sequences encoding full-length native sequence PRO211 and PRO217 have homologies to known proteins having EGF-like domains. Specifically, the cDNA sequence DNA32292-1131 (FIG. 1, SEQ ID NO:1) has certain identify and a Blast score of 209 with PAC6_RAT and certain identify and a Blast score of 206 with Fibulin-1, isoform c precursor. The cDNA sequence DNA33094-1131 (FIG. 3, SEQ ID NO:3) has 36% identity and a Blast score of 336 with eastern newt tenascin, and 37% identity and a Blast score of 331 with human tenascin-X precursor. Accordingly, it is presently believed that PRO211 and PRO217 polypeptides disclosed in the present application are newly identified members of the EGF-like family and possesses properties typical of the EGF-like protein family.

2. Full-length PRO230 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO230. In particular, Applicants have identified and isolated cDNA encoding a PRO230 polypeptide, as disclosed in further detail in the Examples below. Using known programs such as BLAST and FastA sequence alignment computer programs, Applicants found that a cDNA sequence encoding full-length native sequence PRO230 has 48% amino acid identity with the rabbit tubulointerstitial nephritis antigen precursor. Accordingly, it is presently believed that PRO230 polypeptide disclosed in the present application is a newly identified member of the tubulointerstitial nephritis antigen family and possesses the ability to be recognized by human autoantibodies in certain forms of tubulointerstitial nephritis.

3. Full-length PRO232 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO232. In particular, Applicants have identified and isolated cDNA encoding a PRO232 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a portion of the full-length native sequence PRO232 (shown in FIG. 9 and SEQ ID NO:18) has 35% sequence identity with a stem cell surface antigen from Gallus gallus. Accordingly, it is presently believed that the PRO232 polypeptide disclosed in the present application may be a newly identified stem cell antigen.

4. Full-length PRO187 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO187. In particular, Applicants have identified and isolated cDNA encoding a PRO187 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO187 (shown in FIG. 15) has 74% amino acid sequence identity and BLAST score of 310 with various androgen-induced growth factors and FGF-8. Accordingly, it is presently believed that PRO187 polypeptide disclosed in the present application is a newly identified member of the FGF-8 protein family and may possess identify activity or property typical of the FGF-8-like protein family.

5. Full-length PRO265 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO265. In particular, Applicants have identified and isolated cDNA encoding a PRO265 polypeptide, as disclosed in further detail in the Examples below. Using programs such as BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO265 polypeptide have significant homology with the fibromodulin protein and fibromodulin precursor protein. Applicants have also found that the DNA encoding the PRO265 polypeptide has significant homology with platelet glycoprotein V, a member of the leucine rich related protein family involved in skin and wound repair. Accordingly, it is presently believed that PRO265 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses protein protein binding capabilities, as well as be involved in skin and wound repair as typical of this family.

6. Full-length PRO219 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO219. In particular, Applicants have identified and isolated cDNA encoding a PRO219 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO219 polypeptide have significant homology with the mouse and human matrilin-2 precursor polypeptides. Accordingly, it is presently believed that PRO219 polypeptide disclosed in the present application is related to the matrilin-2 precursor polypeptide.

7. Full-length PRO246 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO246. In particular, Applicants have identified and isolated cDNA encoding a PRO246 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a portion of the PRO246 polypeptide has significant homology with the human cell surface protein HCAR. Accordingly, it is presently believed that PRO246 polypeptide disclosed in the present application may be a newly identified membrane-bound virus receptor or tumor cell-specific antigen.

8. Full-length PRO228 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO228. In particular, Applicants have identified and isolated cDNA encoding a PRO228 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO228 polypeptide have significant homology with the EMR1 protein. Applicants have also found that the DNA encoding the PRO228 polypeptide has significant homology with latrophilin, macrophage-restricted cell surface glycoprotein, B0457.1 and leucocyte antigen CD97 precursor. Accordingly, it is presently believed that PRO228 polypeptide disclosed in the present application is a newly identified member of the seven transmembrane superfamily and possesses characteristics and functional properties typical of this family. In particular, it is believed that PRO228 is a new member of the subgroup within this family to which CD97 and EMR1 belong.

9. Full-length PRO533 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO533. In particular, Applicants have identified and isolated cDNA encoding a PRO533 polypeptide, as disclosed in further detail in the Examples below. Using BLAST-2 and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO533 (shown in FIG. 22 and SEQ ID NO:59) has a Blast score of 509 and 53% amino acid sequence identity with fibroblast growth factor (FGF). Accordingly, it is presently believed that PRO533 disclosed in the present application is a newly identified member of the fibroblast growth factor family and may possess activity typical of such polypeptides.

10. Full-length PRO245 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO245. In particular, Applicants have identified and isolated cDNA encoding a PRO245 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a portion of the amino acid sequence of the PRO245 polypeptide has 60% amino acid identity with the human c-myb protein. Accordingly, it is presently believed that the PRO245 polypeptide disclosed in the present application may be a newly identified member of the transmembrane protein tyrosine kinase family.

11. Full-length PRO220, PRO221 and PRO227 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO220, PRO221 and PRO227. In particular, Applicants have identified and isolated cDNAs encoding a PRO220, PRO221 and PRO227 polypeptide, respectively, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, PRO220 has amino acid identity with the amino acid sequence of a leucine rich protein wherein the identity is 87%. PRO220 additionally has amino acid identity with the neuronal leucine rich protein wherein the identity is 55%. The neuronal leucine rich protein is further described in Taguchi, et al., Mol. Brain Res., 35:31-40 (1996).

PRO221 has amino acid identity with the SLIT protein precursor, wherein different portions of these two proteins have the respective percent identities of 39%, 38%, 34%, 31%, and 30%.

PRO227 has amino acid identity with the amino acid sequence of platelet glycoprotein V precursor. The same results were obtained for human glycoprotein V. Different portions of these two proteins show the following percent identities of 30%, 28%, 28%, 31%, 35%, 39% and 27%.

Accordingly, it is presently believed that PRO220, PRO221 and PRO227 polypeptides disclosed in the present application are newly identified members of the leucine rich repeat protein superfamily and that each possesses protein-protein binding capabilities typical of the leucine rich repeat protein superfamily. It is also believed that they have capabilities similar to those of SLIT, the leucine rich repeat protein and human glycoprotein V.

12. Full-length PRO258 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO258. In particular, Applicants have identified and isolated cDNA encoding a PRO258 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO258 polypeptide have significant homology with the CRTAM and poliovirus receptors. Accordingly, it is presently believed that PRO258 polypeptide disclosed in the present application is a newly identified member of the Ig superfamily and possesses virus receptor capabilities or regulates immune function as typical of this family.

13. Full-length PRO266 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO266. In particular, Applicants have identified and isolated cDNA encoding a PRO266 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO266 polypeptide have significant homology with the SLIT protein from Drosophilia. Accordingly, it is presently believed that PRO266 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses ligand-ligand binding activity and neuronal development typical of this family. SLIT has been shown to be useful in the study and treatment of Alzheimer's disease, supra, and thus, PRO266 may have involvement in the study and cure of this disease.

14. Full-length PRO269 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO269. In particular, Applicants have identified and isolated cDNA encoding a PRO269 polypeptide, as disclosed in further detail in the Examples below. Using BLAST, FastA and sequence alignment computer programs, Applicants found that the amino acid sequence encoded by nucleotides 314 to 1783 of the full-length native sequence PRO269 (shown in FIG. 35 and SEQ ID NO:95) has significant homology to human urinary thrombomodulin and various thrombomodulin analogues respectively, to which it was aligned. Accordingly, it is presently believed that PRO269 polypeptide disclosed in the present application is a newly identified member of the thrombomodulin family.

15. Full-length PRO287 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO287. In particular, Applicants have identified and isolated cDNA encoding a PRO287 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO287 polypeptide have significant homology with the type 1 procollagen C-proteinase enhancer protein precursor and type 1 procollagen C-proteinase enhancer protein. Accordingly, it is presently believed that PRO287 polypeptide disclosed in the present application is a newly identified member of the C-proteinase enhancer protein family.

16. Full-length PRO214 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO214. In particular, Applicants have identified and isolated cDNA encoding a PRO214 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO214 polypeptide (shown in FIG. 40 and SEQ ID NO:109) has 49% amino acid sequence identity with HT protein, a known member of the EGF-family. The comparison resulted in a BLAST score of 920, with 150 matching nucleotides. Accordingly, it is presently believed that the PRO214 polypeptide disclosed in the present application is a newly identified member of the family comprising EGF domains and may possess activities or properties typical of the EGF-domain containing family.

17. Full-length PRO317 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO317. In particular, cDNA encoding a PRO317 polypeptide has been identified and isolated, as disclosed in further detail in the Examples below. Using BLAST™ and FastA™ sequence alignment computer programs, it was found that a full-length native-sequence PRO317 (shown in FIG. 42 and SEQ ID NO:114) has 92% amino acid sequence identity with EBAF-1. Further, it is closely aligned with many other members of the TGF- superfamily.

Accordingly, it is presently believed that PRO317 disclosed in the present application is a newly identified member of the TGF- superfamily and may possess properties that are therapeutically useful in conditions of uterine bleeding, etc. Hence, PRO317 may be useful in diagnosing or treating abnormal bleeding involved in gynecological diseases, for example, to avoid or lessen the need for a hysterectomy. PRO317 may also be useful as an agent that affects angiogenesis in general, so PRO317 may be useful in anti-tumor indications, or conversely, in treating coronary ischemic conditions.

Library sources reveal that ESTs used to obtain the consensus DNA for generating PRO317 primers and probes were found in normal tissues (uterus, prostate, colon, and pancreas), in several tumors (colon, brain (twice), pancreas, and mullerian cell), and in a heart with ischemia. PRO317 has shown up in several tissues as well, but it does look to have a greater concentration in uterus. Hence, PRO317 may have a broader use by the body than EBAF-1. It is contemplated that, at least for some indications, PRO317 may have opposite effects from EBAF-1.

18. Full-length PRO301 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO301. In particular, Applicants have identified and isolated cDNA encoding a PRO301 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO301 (shown in FIG. 44 and SEQ ID NO:119) has a Blast score of 246 corresponding to 30% amino acid sequence identity with human A33 antigen precursor. Accordingly, it is presently believed that PRO301 disclosed in the present application is a newly identified member of the A33 antigen protein family and may be expressed in human neoplastic diseases such as colorectal cancer.

19. Full-length PRO224 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO224. In particular, Applicants have identified and isolated cDNA encoding a PRO224 polypeptide, as disclosed in further detail in the Examples below. Using known programs such as BLAST and FastA sequence alignment computer programs, Applicants found that full-length native PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with apolipoprotein E receptor 2906 from homo sapiens. The alignments of different portions of these two polypeptides show amino acid identities of 37%, 36%, 30%, 44%, 44% and 28% respectively. Full-length native PRO224 (FIG. 46, SEQ ID NO:127) also has amino acid identity with very low-density lipoprotein receptor precursor from gall. The alignments of different portions of these two polypeptides show amino acid identities of 38%, 37%, 42%, 33%, and 37% respectively. Additionally, full-length native PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with the chicken oocyte receptor P95 from Gallus gallus. The alignments of different portions of these two polypeptides show amino acid identities of 38%, 37%,42%, 33%, and 37% respectively. Moreover, full-length native PRO224 (FIG. 46, SEQ ID NO:127) has amino acid identity with very low density lipoprotein receptor short form precursor from humans. The alignments of different portions of these two polypeptides show amino acid identities of 32%, 38%, 34%, 45%, and 31%, respectively. Accordingly, it is presently believed that PRO224 polypeptide disclosed in the present application is a newly identified member of the low density lipoprotein receptor family and possesses the structural characteristics required to have the functional ability to recognize and endocytose low density lipoproteins typical of the low density lipoprotein receptor family. (The alignments described above used the following scoring parameters: T=7, S+65, S2=36, Matrix: BLOSUM62.)

20. Full-length PRO222 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO222. In particular, Applicants have identified and isolated cDNA encoding a PRO222 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a sequence encoding full-length native sequence PRO222 (shown in FIG. 48 and SEQ ID NO:132) has 25-26% amino acid identity with mouse complement factor h precursor, has 27-29% amino acid identity with complement receptor, has 25-47% amino acid identity with mouse complement C3b receptor type 2 long form precursor, has 40% amino acid identity with human hypothetical protein kiaa0247. Accordingly, it is presently believed that PRO222 polypeptide disclosed in the present application is a newly identified member of the complement receptor family and possesses activity typical of the complement receptor family.

21. Full-length PRO234 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO234. In particular, Applicants have identified and isolated cDNA encoding a PRO234 polypeptide, as disclosed in further detail in the Examples below. Using BLAST (FastA-format) sequence alignment computer programs, Applicants found that a cDNA sequence encoding full-length native sequence PRO234 has 31% identity and Blast score of 134 with E-selectin precursor. Accordingly, it is presently believed that the PRO234 polypeptides disclosed in the present application are newly identified members of the lectin/selectin family and possess activity typical of the lectin/selectin family.

22. Full-length PRO231 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO23 1. In particular, Applicants have identified and isolated cDNA encoding a PRO231 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that the full-length native sequence PRO231 polypeptide (shown in FIG. 52 and SEQ ID NO:142) has 30% and 31% amino acid identity with human and rat prostatic acid phosphatase precursor proteins, respectively. Accordingly, it is presently believed that the PRO231 polypeptide disclosed in the present application may be a newly identified member of the acid phosphatase protein family.

23. Full-length PRO229 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO229. In particular, Applicants have identified and isolated cDNA encoding a PRO229 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO229 polypeptide have significant homology with antigen wc1.1, M130 antigen, T cell surface glycoprotein CD6 and CD6. It also is related to Sp-alpha. Accordingly, it is presently believed that PRO229 polypeptide disclosed in the present application is a newly identified member of the family containing scavenger receptor homology, a sequence motif found in a number of proteins involved in immune function and thus possesses immune function and/or segments which resist degradation, typical of this family.

24. Full-length PRO238 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO238. In particular, Applicants have identified and isolated cDNA encoding a PRO238 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO238 polypeptide have significant homology with reductases, including oxidoreductase and fatty acyl-CoA reductase. Accordingly, it is presently believed that PRO238 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses reducing activity typical of the reductase family.

25. Full-length PRO233 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO233. In particular, Applicants have identified and isolated cDNA encoding a PRO233 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO233 polypeptide have significant homology with the reductase protein. Applicants have also found that the DNA encoding the PRO233 polypeptide has significant homology with proteins from Caenorhabditis elegans. Accordingly, it is presently believed that PRO233 polypeptide disclosed in the present application is a newly identified member of the reductase family and possesses the ability to effect the redox state of the cell typical of the reductase family.

26. Full-length PRO223 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO223. In particular, Applicants have identified and isolated cDNA encoding a PRO223 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that the PRO223 polypeptide has significant homology with various serine carboxypeptidase polypeptides. Accordingly, it is presently believed that PRO223 polypeptide disclosed in the present application is a newly identified serine carboxypeptidase.

27. Full-length PRO235 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO235. In particular, Applicants have identified and isolated cDNA encoding a PRO235 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO235 polypeptide have significant homology with the various plexin proteins. Accordingly, it is presently believed that PRO235 polypeptide disclosed in the present application is a newly identified member of the plexin family and possesses cell adhesion properties typical of the plexin family.

28. Full-length PRO236 and PRO262 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO236 and PRO262. In particular, Applicants have identified and isolated cDNA encoding PRO236 and PRO262 polypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO236 and PRO262 polypeptides have significant homology with various β-galactosidase and β-galactosidase precursor polypeptides. Accordingly, it is presently believed that the PRO236 and PRO262 polypeptides disclosed in the present application are newly identified β-galactosidase homologs.

29. Full-length PRO239 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO239. In particular, Applicants have identified and isolated cDNA encoding a PRO239 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO239 polypeptide have significant homology with densin proteins. Accordingly, it is presently believed that PRO239 polypeptide disclosed in the present application is a newly identified member of the densin family and possesses cell adhesion and the ability to effect synaptic processes as is typical of the densin family.

30. Full-length PRO257 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO257. In particular, Applicants have identified and isolated cDNA encoding a PRO257 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO257 polypeptide have significant homology with the ebnerin precursor and ebnerin protein. Accordingly, it is presently believed that PRO257 polypeptide disclosed in the present application is a newly identified protein member which is related to the ebnerin protein.

31. Full-length PRO260 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO260. In particular, Applicants have identified and isolated cDNA encoding a PRO260 polypeptide, as disclosed in further detail in the Examples below. Using programs such as BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO260 polypeptide have significant homology with the alpha-1-fucosidase precursor. Accordingly, it is presently believed that PRO260 polypeptide disclosed in the present application is a newly identified member of the fucosidase family and possesses enzymatic activity related to fucose residues typical of the fucosidase family.

32. Full-length PRO263 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO263. In particular, Applicants have identified and isolated cDNA encoding a PRO263 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO263 polypeptide have significant homology with the CD44 antigen and related proteins. Accordingly, it is presently believed that PRO263 polypeptide disclosed in the present application is a newly identified member of the CD44 antigen family and possesses at least one of the properties associated with these antigens, i.e., cancer and HIV marker, cell-cell or cell-matrix interactions, regulating cell traffic, lymph node homing, transmission of growth signals, and presentation of chemokines and growth facors to traveling cells.

33. Full-length PRO270Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO270. In particular, Applicants have identified and isolated cDNA encoding a PRO270 polypeptide, as disclosed in further detail in the Examples below. Using BLAST, FastA and sequence alignment computer programs, Applicants found that that various portions of the PRO270 polypeptide have significant homology with various thioredoxin proteins. Accordingly, it is presently believed that PRO270 polypeptide disclosed in the present application is a newly identified member of the thioredoxin family and possesses the ability to effect reduction-oxidation (redox) state typical of the thioredoxin family.

34. Full-length PRO271 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO271. In particular, Applicants have identified and isolated cDNA encoding a PRO271 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that the PRO271 polypeptide has significant homology with various link proteins and precursors thereof. Accordingly, it is presently believed that PRO271 polypeptide disclosed in the present application is a newly identified link protein homolog.

35. Full-length PRO272 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO272. In particular, Applicants have identified and isolated cDNA encoding a PRO272 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO272 polypeptide have significant homology with the human reticulocalbin protein and its precursors. Applicants have also found that the DNA encoding the PRO272 polypeptide has significant homology with the mouse reticulocalbin precursor protein. Accordingly, it is presently believed that PRO272 polypeptide disclosed in the present application is a newly identified member of the reticulocalbin family and possesses the ability to bind calcium typical of the reticulocalbin family.

36. Full-length PRO294 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO294. In particular, Applicants have identified and isolated cDNA encoding a PRO294 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO294 polypeptide have significant homology with the various portions of a number of collagen proteins. Accordingly, it is presently believed that PRO294 polypeptide disclosed in the present application is a newly identified member of the collagen family.

37. Full-length PRO295 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO295. In particular, Applicants have identified and isolated cDNA encoding a PRO295 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO295 polypeptide have significant homology with integrin proteins. Accordingly, it is presently believed that PRO295 polypeptide disclosed in the present application is a newly identified member of the integrin family and possesses cell adhesion typical of the integrin family.

38. Full-length PRO293 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO293. In particular, Applicants have identified and isolated cDNA encoding a PRO293 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that portions of the PRO293 polypeptide have significant homology with the neuronal leucine rich repeat proteins 1 and 2, (NLRR-1 and NLRR-2), particularly NLRR-2. Accordingly, it is presently believed that PRO293 polypeptide disclosed in the present application is a newly identified member of the neuronal leucine rich repeat protein family and possesses ligand-ligand binding activity typical of the NRLL protein family.

39. Full-length PRO247 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO247. In particular, Applicants have identified and isolated cDNA encoding a PRO247 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO247 polypeptide have significant homology with densin. Applicants have also found that the DNA encoding the PRO247 polypeptide has significant homology with a number of other proteins, including KIAA0231. Accordingly, it is presently believed that PRO247 polypeptide disclosed in the present application is a newly identified member of the leucine rich repeat family and possesses ligand binding abilities typical of this family.

40. Full-length PRO302, PRO303, PRO304, PRO307 and PRO343 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO302, PRO303, PRO304, PRO307 and PRO343. In particular, Applicants have identified and isolated cDNA encoding PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides have significant homology with various protease proteins. Accordingly, it is presently believed that the PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides disclosed in the present application are newly identified protease proteins.

41. Full-length PRO328 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO328. In particular, Applicants have identified and isolated cDNA encoding a PRO328 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO328 polypeptide have significant homology with the human glioblastoma protein (“GLIP”). Further, Applicants found that various portions of the PRO328 polypeptide have significant homology with the cysteine rich secretory protein (“CRISP”) as identified by BLAST homology [ECCRISP3_(—)1, S68683, and CRS3_HUMAN]. Accordingly, it is presently believed that PRO328 polypeptide disclosed in the present application is a newly identified member of the GLIP or CRISP families and possesses transcriptional regulatory activity typical of the GLIP or CRISP families.

42. Full-length PRO335, PRO331 and PRO326 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO335, PRO331 or PRO326. In particular, Applicants have identified and isolated cDNA encoding a PRO335, PRO331 or PRO326 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO335, PRO331 or PRO326 polypeptide have significant homology with LIG-1, ALS and in the case of PRO331, additionally, decorin. Accordingly, it is presently believed that the PRO335, PRO331 and PRO326 polypeptides disclosed in the present application are newly identified members of the leucine rich repeat superfamily, and particularly, are related to LIG-1 and possess the biological functions of this family as discussed and referenced herein.

43. Full-length PRO332 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO332. In particular, Applicants have identified and isolated cDNA encoding PRO332 polypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO332 (shown in FIG. 108 and SEQ ID NO:310) has about 3040% amino acid sequence identity with a series of known proteoglycan sequences, including, for example, fibromodulin and fibromodulin precursor sequences of various species (FMOD_BOVIN, FMOD_CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN, P_R36773), osteomodulin sequences (AB000114₁₃ 1, AB007848_1), decorin sequences (CFU83141_(—)1, OCU03394_(—)1, P R42266, P_R42267, P_R42260, P_R89439), keratan sulfate proteoglycans (BTU48360_(—)1, AF022890_(—)1), corneal proteoglycan (AF022256_(—)1), and bone/cartilage proteoglycans and proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN). Accordingly, it is presently believed that PRO332 disclosed in the present application is a new proteoglycan-type molecule, and may play a role in regulating extracellular matrix, cartilage, and/or bone function.

44. Full-length PRO334 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO334. In particular, Applicants have identified and isolated cDNA encoding a PRO334 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO334 polypeptide have significant homology with fibulin and fibrillin. Accordingly, it is presently believed that PRO334 polypeptide disclosed in the present application is a newly identified member of the epidermal growth factor family and possesses properties and activities typical of this family.

45. Full-length PRO346 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO346. In particular, Applicants have identified and isolated cDNA encoding a PRO346 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO346 (shown in FIG. 112 and SEQ ID NO:320) has 28% amino acid sequence identity with carcinoembryonic antigen. Accordingly, it is presently believed that PRO346 disclosed in the present application is a newly identified member of the carcinoembryonic protein family and may be expressed in association with neoplastic tissue disorders.

46. Full-length PRO268 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO268. In particular, Applicants have identified and isolated cDNA encoding a PRO268 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that portions of the PRO268 polypeptide have significant homology with the various protein disulfide isomerase proteins. Accordingly, it is presently believed that PRO268 polypeptide disclosed in the present application is a homolog of the protein disulfide isomerase p5 protein.

47. Full-length PRO330 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO330. In particular, Applicants have identified and isolated cDNA encoding a PRO330 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO330 polypeptide have significant homology with the murine prolyl 4-hydroxylase alpha-II subunit protein. Accordingly, it is presently believed that PRO330 polypeptide disclosed in the present application is a novel prolyl 4-hydroxylase subunit polypeptide.

48. Full-length PRO339 and PRO310 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO339 and PRO310. In particular, Applicants have identified and isolated cDNA encoding a PRO339 polypeptide, as disclosed in further detail in the Examples below. Applicants have also identified and isolated cDNA encoding a PRO310 polypeptide, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that various portions of the PRO339 and PRO310 polypeptides have significant homology with small secreted proteins from C. elegans and are distantly related to fringe. PRO339 also shows homology to collagen-like polymers. Sequences which were used to identify PRO310, designated herein as DNA40533 and DNA42267, also show homology to proteins from C. elegans. Accordingly, it is presently believed that the PRO339 and PRO310 polypeptides disclosed in the present application are newly identified member of the family of proteins involved in development, and which may have regulatory abilities similar to the capability of fringe to regulate serrate.

49. Full Length PRO244 Polypeptides

The present invention provides newly identified and isolated nucleotide sequences encoding C-type lectins referred to in the present application as PRO244. In particular, applicants have identified and isolated cDNA encoding PRO244 polypeptides, as disclosed in further detail in the Examples below. Using BLAST and FastA sequence alignment computer programs, Applicants found that a full-length native sequence PRO244 (shown in FIG. 122 and SEQ ID NO:377) has 43% amino acid sequence identity with the hepatic lectin gallus gallus (LECH-CHICK), and 42% amino acid sequence identity with an HIV gp120 binding C-type lectin (A46274). Accordingly, it is presently believed that PRO244 disclosed in the present application is a newly identified member of the C-lectin superfamily and may play a role in immune function, apoptosis, or in the pathogenesis of atherosclerosis. In addition, PRO244 may be useful in identifying tumor-associated epitopes.

B. PRO Polypeptide Variants

In addition to the full-length native sequence PRO polypeptides described herein, it is contemplated that PRO variants can be prepared. PRO variants can be prepared by introducing appropriate nucleotide changes into the PRO DNA, and/or by synthesis of the desired PRO polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of the PRO, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.

Variations in the native full-length sequence PRO or in various domains of the PRO described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO that results in a change in the amino acid sequence of the PRO as compared with the native sequence PRO. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.

PRO polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO polypeptide.

PRO fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating PRO fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5′ and 3′ primers in the PCR. Preferably, PRO polypeptide fragments share at least one biological and/or immunological activity with the native PRO polypeptide disclosed herein.

In particular embodiments, conservative substitutions of interest are shown in Table 6 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 6, or as further described below in reference to amino acid classes, are introduced and the products screened.

TABLE 6 Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) val; leu; ile val Arg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu glu Cys (C) ser ser Gln (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His (H) asn; gln; lys; arg arg Ile (I) leu; val; met; ala; phe; leu norleucine Leu (L) norleucine; ile; val; ile met; ala; phe Lys (K) arg; gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyr leu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; leu ala; norleucine

Substantial modifications in function or immunological identity of the PRO polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gln, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.

The variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)], restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the PRO variant DNA.

Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glycine, serine, and cysteine. Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science, 244: 1081-1085 (1989)]. Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.

C. Modifications of PRO

Covalent modifications of PRO are included within the scope of this invention. One type of covalent modification includes reacting targeted amino acid residues of a PRO polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues of the PRO. Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO antibodies, and vice-versa. Commonly used crosslinking agents include, e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.

Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the α-amino groups of lysine, arginine, and histidine side chains [T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

Another type of covalent modification of the PRO polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide. “Altering the native glycosylation pattern” is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.

Addition of glycosylation sites to the PRO polypeptide may be accomplished by altering the amino acid sequence. The alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO (for O-inked glycosylation sites). The PRO amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the PRO polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

Another means of increasing the number of carbohydrate moieties on the PRO polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published Sep. 11, 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981).

Removal of carbohydrate moieties present on the PRO polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol., 138:350 (1987).

Another type of covalent modification of PRO comprises linking the PRO polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

The PRO of the present invention may also be modified in a way to form a chimeric molecule comprising PRO fused to another, heterologous polypeptide or amino acid sequence.

In one embodiment, such a chimeric molecule comprises a fusion of the PRO with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl-terminus of the PRO. The presence of such epitope-tagged forms of the PRO can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, G4, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, 255:192-194 (1992)]; an α-tubulin epitope peptide [Skinner et al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. U.S.A., 87:6393-6397 (1990)].

In an alternative embodiment, the chimeric molecule may comprise a fusion of the PRO with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule (also referred to as an “immunoadhesin”), such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO polypeptide in place of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27, 1995.

D. Preparation of PRO

The description below relates primarily to production of PRO by culturing cells transformed or transfected with a vector containing PRO nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare PRO. For instance, the PRO sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, Calif.) using manufacturer's instructions. Various portions of the PRO may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO.

1. Isolation of DNA Encoding PRO

DNA encoding PRO may be obtained from a cDNA library prepared from tissue believed to possess the PRO mRNA and to express it at a detectable level. Accordingly, human PRO DNA can be conveniently obtained from a cDNA library prepared from human tissue, such as described in the Examples. The PRO-encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).

Libraries can be screened with probes (such as antibodies to the PRO or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding PRO is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

The Examples below describe techniques for screening a cDNA library. The oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like ³²P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.

Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein.

Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.

2. Selection and Transformation of Host Cells

Host cells are transfected or transformed with expression or cloning vectors described herein for PRO production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.

Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published Jun. 29, 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transfections have been described in U.S. Pat. No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., J. Bact., 130:946(1977) and Hsiao et al., Proc. Natl. Acad. Sci. (U.S.A.), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).

Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli. Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41P disclosed in DD 266,710 published Apr. 12, 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA ; E. coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonAptr3phoA E15 (argF-lac)169 degP ompT kan^(r) ; E. coli W3110 strain 37D6, which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan^(r) , E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued Aug. 7, 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.

In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published May 2, 1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 737 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. U.S.A., 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published Oct. 31, 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published Jan. 10, 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. U.S.A., 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).

Suitable host cells for the expression of glycosylated PRO are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art.

3. Selection and Use of a Replicable Vector

The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan.

The PRO may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the PRO-encoding DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, 1pp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveromyces α-factor leaders, the latter described in U.S. Pat. No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published Apr. 4, 1990), or the signal described in WO 90/13646 published Nov. 15, 1990. In mammalian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.

Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 2μ plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.

Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.

An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. U.S.A., 77:4216 (1980). A suitable selection gene for use in yeast is the trp1 gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)].

Expression and cloning vectors usually contain a promoter operably linked to the PRO-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the β-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. U.S.A., 80:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO.

Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.

PRO transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published Jul. 5, 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.

Transcription of a DNA encoding the PRO by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, α-fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5′ or 3′ to the PRO coding sequence, but is preferably located at a site 5′ from the promoter.

Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5′ and, occasionally 3′, untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO.

Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO in recombinant vertebrate cell culture are described in Gething et al., Nature 293:620-625 (1981); Mantei et al., Nature, 281:4046 (1979); EP 117,060; and EP 117,058.

4. Detecting Gene Amplification/Expression

Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. U.S.A., 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.

Gene expression, alternatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO DNA and encoding a specific antibody epitope.

5. Purification of Polypeptide

Forms of PRO may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X 100) or by enzymatic cleavage. Cells employed in expression of PRO can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.

It may be desired to purify PRO from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAE; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO. Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular PRO produced.

E. Uses for PRO

Nucleotide sequences (or their complement) encoding PRO have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. PRO nucleic acid will also be useful for the preparation of PRO polypeptides by the recombinant techniques described herein.

The full-length native sequence PRO gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO or PRO from other species) which have a desired sequence identity to the native PRO sequence disclosed herein. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO. By way of example, a screening method will comprise isolating the coding region of the PRO gene using the known DNA sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels, including radionucleotides such as ³²P or ³⁵S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the PRO gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described in further detail in the Examples below.

Any EST sequences disclosed in the present application may similarly be employed as probes, using the methods disclosed herein.

Other useful fragments of the PRO nucleic acids include antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO mRNA (sense) or PRO DNA (antisense) sequences. Antisense or sense oligonucleotides, according to the present invention, comprise a fragment of the coding region of PRO DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides. The ability to derive an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al. (BioTechniques 6:958, 1988).

Binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means. The antisense oligonucleotides thus may be used to block expression of PRO proteins. Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases. Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.

Other examples of sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine). Further still, intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence.

Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaPO₄-mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus. In a preferred procedure, an antisense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo. Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753. Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors. Preferably, conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell.

Alternatively, a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448. The sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase.

Antisense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about 15 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more.

The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO coding sequences.

Nucleotide sequences encoding a PRO can also be used to construct hybridization probes for mapping the gene which encodes that PRO and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries.

When the coding sequences for PRO encode a protein which binds to another protein (example, where the PRO is a receptor), the PRO can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO can be used to isolate correlative ligand(s). Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO or a receptor for PRO. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.

Nucleic acids which encode PRO or its modified forms can also be used to generate either transgenic animals or “knock out” animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. In one embodiment, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO. Methods for generating transgenic animals, particularly animals such as mice or rats, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009. Typically, particular cells would be targeted for PRO transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding PRO introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding PRO. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition.

Alternatively, non-human homologues of PRO can be used to construct a PRO “knock out” animal which has a defective or altered gene encoding PRO as a result of homologous recombination between the endogenous gene encoding PRO and altered genomic DNA encoding PRO introduced into an embryonic stem cell of the animal. For example, cDNA encoding PRO can be used to clone genomic DNA encoding PRO in accordance with established techniques. A portion of the genomic DNA encoding PRO can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., Cell, 69:915 (1992)]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells:A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a “knock out” animal. Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the PRO polypeptide.

Nucleic acid encoding the PRO polypeptides may also be used in gene therapy. In gene therapy applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. “Gene therapy” includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Natl. Acad. Sci. U.S.A. 83:41434146 [1986]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.

There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. U.S.A. 87, 3410-3414 (1990). For review of gene marking and gene therapy protocols see Anderson et al., Science 256, 808-813 (1992).

The PRO polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers.

The nucleic acid molecules encoding the PRO polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to identify new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data are presently available. Each PRO nucleic acid molecule of the present invention can be used as a chromosome marker.

The PRO polypeptides and nucleic acid molecules of the present invention may also be used for tissue typing, wherein the PRO polypeptides of the present invention may be differentially expressed in one tissue as compared to another. PRO nucleic acid molecules will find use for generating probes for PCR, Northern analysis, Southern analysis and Western analysis.

The PRO polypeptides described herein may also be employed as therapeutic agents. The PRO polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN™, PLURONICS™ or PEG.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.

Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

The route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes, topical administration, or by sustained release systems.

Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti, J. and Chappell, W. “The use of interspecies scaling in toxicokinetics” In Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96.

When in vivo administration of a PRO polypeptide or agonist or antagonist thereof is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.

Where sustained-release administration of a PRO polypeptide is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the PRO polypeptide, microencapsulation of the PRO polypeptide is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon-(rhIFN- ), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Hora et al., Bio/Technology, 8:755-758 (1990); Cleland, “Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat. No. 5,654,010.

The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, “Controlled release of bioactive agents from lactide/glycolide polymer,” in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drum Delivery Systems (Marcel Dekker: New York, 1990), pp. 1-41.

This invention encompasses methods of screening compounds to identify those that mimic the PRO polypeptide (agonists) or prevent the effect of the PRO polypeptide (antagonists). Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO polypeptides encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptides with other cellular proteins. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.

The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art.

All assays for antagonists are common in that they call for contacting the drug candidate with a PRO polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact.

In binding assays, the interaction is binding and the complex formed can be isolated or detected in the reaction mixture. In a particular embodiment, the PRO polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments. Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the PRO polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label immobilized on the surface indicates that complexing occurred. Where the originally non-immobilized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.

If the candidate compound interacts with but does not bind to a particular PRO polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song, Nature (London), 340:245-246 (1989); Chien et al., Proc. Natl. Acad. Sci. U.S.A., 88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. U.S.A., 89: 5789-5793 (1991). Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the “two-hybrid system”) takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain. The expression of a GAL1-lacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™) for identifying protein-protein interactions between two specific proteins using the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions.

Compounds that interfere with the interaction of a gene encoding a PRO polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture, to serve as positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reaction(s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner.

To assay for antagonists, the PRO polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO polypeptide indicates that the compound is an antagonist to the PRO polypeptide. Alternatively, antagonists may be detected by combining the PRO polypeptide and a potential antagonist with membrane-bound PRO polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay. The PRO polypeptide can be labeled, such as by radioactivity, such that the number of PRO polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991). Preferably, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the PRO polypeptide. Transfected cells that are grown on glass slides are exposed to labeled PRO polypeptide. The PRO polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor.

As an alternative approach for receptor identification, labeled PRO polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film. The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro-sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor.

In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with labeled PRO polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured.

More specific examples of potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with PRO polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments. Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the PRO polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO polypeptide.

Another potential PRO polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation. Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5′ coding portion of the polynucleotide sequence, which encodes the mature PRO polypeptides herein, is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix - see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan et al., Science, 251:1360 (1991)), thereby preventing transcription and the production of the PRO polypeptide. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PRO polypeptide (antisense—Okano, Neurochem., 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, Fla., 1988). The oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the PRO polypeptide. When antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation site, e.g., between about −10 and +10 positions of the target gene nucleotide sequence, are preferred.

Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO polypeptide, thereby blocking the normal biological activity of the PRO polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds.

Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469471 (1994), and PCT publication No. WO 97/33551 (published Sep. 18, 1997).

Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides. The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO 97/33551, supra.

These small molecules can be identified by any one or more of the screening assays discussed hereinabove and/or by any other screening techniques well known for those skilled in the art.

With regard to the PRO211 and PRO217 polypeptide, therapeutic indications include disorders associated with the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration and congenital microvillus atrophy), skin diseases associated with abnormal keratinocyte differentiation (e.g., psoriasis, epithelial cancers such as lung squamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.

Since the PRO232 polypeptide and nucleic acid encoding it possess sequence homology to a cell surface stem cell antigen and its encoding nucleic acid, probes based upon the PRO232 nucleotide sequence may be employed to identify other novel stem cell surface antigen proteins. Soluble forms of the PRO232 polypeptide may be employed as antagonists of membrane bound PRO232 activity both in vitro and in vivo. PRO232 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PRO232 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay. Moreover, the PRO232 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.

With regard to the PRO187 polypeptides disclosed herein, FGF-8 has been implicated in cellular differentiation and embryogenesis, including the patterning which appears during limb formation. FGF-8 and the PRO187 molecules of the invention therefore are likely to have potent effects on cell growth and development. Diseases which relate to cellular growth and differentiation are therefore suitable targets for therapeutics based on functionality similar to FGF-8. For example, diseases related to growth or survival of nerve cells including Parkinson's disease, Alzheimer's disease, ALS, neuropathies. Additionally, disease related to uncontrolled cell growth, e.g., cancer, would also be expected therapeutic targets.

With regard to the PRO265 polypeptides disclosed herein, other methods for use with PRO265 are described in U.S. Pat. 5,654,270 to Ruoslahti et al. In particular, PRO265 can be used in comparison with the fibromodulin disclosed therein to compare its effects on reducing dermal scarring and other properties of the fibromodulin described therein including where it is located and with what it binds and does not.

The PRO219 polypeptides of the present invention which play a regulatory role in the blood coagulation cascade may be employed in vivo for therapeutic purposes as well as for in vitro purposes. Those of ordinary skill in the art will well know how to employ PRO219 polypeptides for such uses.

The PRO246 polypeptides of the present invention which serve as cell surface receptors for one or more viruses will find other uses. For example, extracellular domains derived from these PRO246 polypeptides may be employed therapeutically in vivo for lessening the effects of viral infection. Those PRO246 polypeptides which serves as tumor specific antigens may be exploited as therapeutic targets for anti-tumor drugs, and the like. Those of ordinary skill in the art will well know how to employ PRO246 polypeptides for such uses.

Assays in which connective growth factor and other growth factors are usually used should be performed with PRO261. An assay to determine whether TGF beta induces PRO261, indicating a role in cancer is performed as known in the art. Wound repair and tissue growth assays are also performed with PRO261. The results are applied accordingly.

PRO228 polypeptides should be used in assays in which EMR1, CD97 and latrophilin would be used in to determine their relative activities. The results can be applied accordingly. For example, a competitive binding assay with PRO228 and CD97 can be performed with the ligand for CD97, CD55.

Native PRO533 is a 216 amino acid polypeptide of which residues 1-22 are the signal sequence. Residues 3 to 216 have a Blast score of 509, corresponding to 53% homology to fibroblast growth factor. At the nucleotide level, DNA47412, the EST from which PCR oligos were generated to isolate the full length DNA49435-1219, has been observed to map to 11p15. Sequence homology to the 11p15 locus would indicate that PRO533 may have utility in the treatment of Usher Syndrome or Atrophia areata.

As mentioned previously, fibroblast growth factors can act upon cells in both a mitogenic and non-mitogenic manner. These factors are mitogenic for a wide variety of normal diploid mesoderm-derived and neural crest-derived cells, inducing granulosa cells, adrenal cortical cells, chrondrocytes, myoblasts, corneal and vascular endothelial cells (bovine or human), vascular smooth muscle cells, lens, retina and prostatic epithelial cells, oligodendrocytes, astrocytes, chrondocytes, myoblasts and osteoblasts.

Non-mitogenic actions of fibroblast growth factors include promotion of cell migration into a wound area (chemotaxis), initiation of new blood vessel formulation (angiogenesis), modulation of nerve regeneration and survival (neurotrophism), modulation of endocrine functions, and stimulation or suppression of specific cellular protein expression, extracellular matrix production and cell survival. Baird, A. & Bohlen, P., Handbook of Exp. Phrmacol. 95(1): 369-418 (1990). These properties provide a basis for using fibroblast growth factors in therapeutic approaches to accelerate wound healing, nerve repair, collateral blood vessel formation, and the like. For example, fibroblast growth factors, have been suggested to minimize myocardium damage in heart disease and surgery (U.S. Pat. No. 4,378,437).

Since the PRO245 polypeptide and nucleic acid encoding it possess sequence homology to a transmembrane protein tyrosine kinase protein and its encoding nucleic acid, probes based upon the PRO245 nucleotide sequence may be employed to identify other novel transmembrane tyrosine kinase proteins. Soluble forms of the PRO245 polypeptide may be employed as antagonists of membrane bound PRO245 activity both in vitro and in vivo. PRO245 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PRO245 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay. Moreover, the PRO245 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.

PRO220, PRO221 and PRO227 all have leucine rich repeats. Additionally, PRO220 and PRO221 have homology to SLIT and leucine rich repeat protein. Therefore, these proteins are useful in assays described in the literature, supra, wherein the SLIT and leucine rich repeat protein are used. Regarding the SLIT protein, PRO227 can be used in an assay to determine the affect of PRO227 on neurodegenerative disease. Additionally, PRO227 has homology to human glycoprotein V. In the case of PRO227, this polypeptide is used in an assay to determine its affect on bleeding, clotting, tissue repair and scarring.

The PRO266 polypeptide can be used in assays to determine if it has a role in neurodegenerative diseases or their reversal.

PRO269 polypeptides and portions thereof which effect the activity of thrombin may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications. In addition, PRO269 polypeptides and portions thereof may have therapeutic use as an antithrombotic agent with reduced risk for hemorrhage as compared with heparin. Peptides having homology to thrombomodulin are particularly desirable.

PRO287 polypeptides and portions thereof which effect the activity of bone morphogenic protein “BMP1”/procollagen C-proteinase (PCP) may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications. In addition, PRO287 polypeptides and portions thereof may have therapeutic applications in wound healing and tissue repair. Peptides having homology to procollagen C-proteinase enhancer protein and its precursor may also be used to induce bone and/or cartilage formation and are therefore of particular interest to the scientific and medical communities.

Therapeutic indications for PRO214 polypeptides include disorders associated with the preservation and maintenance of gastrointestinal mucosa and the repair of acute and chronic mucosal lesions (e.g., enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration and congenital microvillus atrophy), skin diseases associated with abnormal keratinocyte differentiation (e.g., psoriasis, epithelial cancers such as lung squamous cell carcinoma, epidermoid carcinoma of the vulva and gliomas.

Studies on the generation and analysis of mice deficient in members of the TGF—superfamily are reported in Matzuk, Trends in Endocrinol, and Metabol., 6: 120-127 (1995).

The PRO317 polypeptide, as well as PRO317-specific antibodies, inhibitors, agonists, receptors, or their analogs, herein are useful in treating PRO317-associated disorders. Hence, for example, they may be employed in modulating endometrial bleeding angiogenesis, and may also have an effect on kidney tissue. Endometrial bleeding can occur in gynecological diseases such as endometrial cancer as abnormal bleeding. Thus, the compositions herein may find use in diagnosing and treating abnormal bleeding conditions in the endometrium, as by reducing or eliminating the need for a hysterectomy. The molecules herein may also find use in angiogenesis applications such as anti-tumor indications for which the antibody against vascular endothelial growth factor is used, or, conversely, ischemic indications for which vascular endothelial growth factor is employed.

Bioactive compositions comprising PRO317 or agonists or antagonists thereof may be administered in a suitable therapeutic dose determined by any of several methodologies including clinical studies on mammalian species to determine maximal tolerable dose and on normal human subjects to determine safe dose. Additionally, the bioactive agent may be complexed with a variety of well established compounds or compositions which enhance stability or pharmacological properties such as half-life. It is contemplated that the therapeutic, bioactive composition may be delivered by intravenous infusion into the bloodstream or any other effective means which could be used for treating problems of the kidney, uterus, endometrium, blood vessels, or related tissue, e.g., in the heart or genital tract.

Dosages and administration of PRO317, PRO317 agonist, or PRO317 antagonist in a pharmaceutical composition may be determined by one of ordinary skill in the art of clinical pharmacology or pharmacokinetics. See, for example, Mordenti and Rescigno, Pharmaceutical Research, 9:17-25 (1992); Morenti et al., Pharmaceutical Research, 8:1351-1359 (1991); and Mordenti and Chappell, “The use of interspecies scaling in toxicokinetics” in Toxicokinetics and New Drug Development, Yacobi et al. (eds) (Pergamon Press: NY, 1989), pp. 42-96. An effective amount of PRO317, PRO317 agonist, or PRO317 antagonist to be employed therapeutically will depend, for example, upon the therapeutic objectives, the route of administration, and the condition of the mammal. Accordingly, it will be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. A typical daily dosage might range from about 10 ng/kg to up to 100 mg/kg of the mammal's body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day. Typically, the clinician will administer PRO317, PRO317 agonist, or PRO317 antagonist, until a dosage is reached that achieves the desired effect for treatment of the above mentioned disorders.

PRO317 or an PRO317 agonist or PRO317 antagonist may be administered alone or in combination with another to achieve the desired pharmacological effect. PRO317 itself, or agonists or antagonists of PRO317 can provide different effects when administered therapeutically. Such compounds for treatment will be formulated in a nontoxic, inert, pharmaceutically acceptable aqueous carrier medium preferably at a pH of about 5 to 8, more preferably 6 to 8, although the pH may vary according to the characteristics of the PRO317, agonist, or antagonist being formulated and the condition to be treated. Characteristics of the treatment compounds include solubility of the molecule, half-life, and antigenicity/immunogenicity; these and other characteristics may aid in defining an effective carrier.

PRO317 or PRO317 agonists or PRO317 antagonists may be delivered by known routes of administration including but not limited to topical creams and gels; transmucosal spray and aerosol, transdermal patch and bandage; injectable, intravenous, and lavage formulations; and orally administered liquids and pills, particularly formulated to resist stomach acid and enzymes. The particular formulation, exact dosage, and route of administration will be determined by the attending physician and will vary according to each specific situation.

Such determinations of administration are made by considering multiple variables such as the condition to be treated, the type of mammal to be treated, the compound to be administered, and the pharmacokinetic profile of the particular treatment compound. Additional factors which may be taken into account include disease state (e.g. severity) of the patient, age, weight, gender, diet, time of administration, drug combination, reaction sensitivities, and tolerance/response to therapy. Long-acting treatment compound formulations (such as liposomally encapsulated PRO317 or PEGylated PRO317 or PRO317 polymeric microspheres, such as polylactic acid-based microspheres) might be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular treatment compound.

Normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 μg/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. Nos. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting the uterus, for example, may necessitate delivery in a manner different from that to another organ or tissue, such as cardiac tissue.

Where sustained-release administration of PRO317 is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of PRO317, microencapsulation of PRO317 is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2: 795-799 (1996); Yasuda, Biomed. Ther., 27: 1221-1223 (1993); Hora et al., Bio/Technology 8: 755-758 (1990); Cleland, “Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems,” in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO 96140072, WO 96/07399; and U.S. Pat. No. 5,654,010.

It is contemplated that conditions or diseases of the uterus, endometrial tissue, or other genital tissues or cardiac tissues may precipitate damage that is treatable with PRO317 or PRO317 agonist where PRO317 expression is reduced in the diseased state; or with antibodies to PRO317 or other PRO317 antagonists where the expression of PRO317 is increased in the diseased state. These conditions or diseases may be specifically diagnosed by the probing tests discussed above for physiologic and pathologic problems which affect the function of the organ.

The PRO317, PRO317 agonist, or PRO317 antagonist may be administered to a mammal with another biologically active agent, either separately or in the same formulation to treat a common indication for which they are appropriate. For example, it is contemplated that PRO317 can be administered together with EBAF-1 for those indications on which they demonstrate the same qualitative biological effects. Alternatively, where they have opposite effects, EBAF-1 may be administered together with an antagonist to PRO317, such as an anti-PRO317 antibody. Further, PRO317 may be administered together with VEGF for coronary ischemia where such indication is warranted, or with an anti-VEGF for cancer as warranted, or, conversely, an antagonist to PRO317 may be administered with VEGF for coronary ischemia or with anti-VEGF to treat cancer as warranted. These administrations would be in effective amounts for treating such disorders.

Native PRO301 (SEQ ID NO:119) has a Blast score of 246 and 30% homology at residues 24 to 282 of FIG. 44 with A33_HUMAN, an A33 antigen precursor. A33 antigen precursor, as explained in the Background is a tumor-specific antigen, and as such, is a recognized marker and therapeutic target for the diagnosis and treatment of colon cancer. The expression of tumor-specific antigens is often associated with the progression of neoplastic tissue disorders. Native PRO301 (SEQ ID NO:119) and A33_HUMAN also show a Blast score of 245 and 30% homology at residues 21 to 282 of FIG. 44 with A33_HUMAN, the variation dependent upon how spaces are inserted into the compared sequences. Native PRO301 (SEQ ID NO:119) also has a Blast score of 165 and 29% homology at residues 60 to 255 of FIG. 44 with HS46KDA_(—)1, a human coxsackie and adenovirus receptor protein, also known as cell surface protein HCAR. This region of PRO301 also shows a similar Blast score and homology with HSU90716_(—)1. Expression of such proteins is usually associated with viral infection and therapeutics for the prevention of such infection may be accordingly conceived. As mentioned in the Background, the expression of viral receptors is often associated with neoplastic tumors.

Therapeutic uses for the PRO234 polypeptides of the invention includes treatments associated with leukocyte homing or the interaction between leukocytes and the endothelium during an inflammatory response. Examples include asthma, rheumatoid arthritis, psoriasis and multiple sclerosis.

Since the PRO231 polypeptide and nucleic acid encoding it possess sequence homology to a putative acid phosphatase and its encoding nucleic acid, probes based upon the PRO231 nucleotide sequence may be employed to identify other novel phosphatase proteins. Soluble forms of the PRO231 polypeptide may be employed as antagonists of membrane bound PRO231 activity both in vitro and in vivo. PRO231 polypeptides may be employed in screening assays designed to identify agonists or antagonists of the native PRO231 polypeptide, wherein such assays may take the form of any conventional cell-type or biochemical binding assay. Moreover, the PRO231 polypeptide may serve as a molecular marker for the tissues in which the polypeptide is specifically expressed.

PRO229 polypeptides can be fused with peptides of interest to determine whether the fusion peptide has an increased half-life over the peptide of interest. The PRO229 polypeptides can be used accordingly to increase the half-life of polypeptides of interest. Portions of PRO229 which cause the increase in half-life are an embodiment of the invention herein.

PRO238 can be used in assays which measure its ability to reduce substrates, including oxygen and Aceyl-CoA, and particularly, measure PRO238's ability to produce oxygen free radicals. This is done by using assays which have been previously described. PRO238 can further be used to assay for candidates which block, reduce or reverse its reducing abilities. This is done by performing side by side assays where candidates are added in one assay having PRO238 and a substrate to reduce, and not added in another assay, being the same but for the lack of the presence of the candidate.

PRO233 polypeptides and portions thereof which have homology to reductase may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel reductase proteins and related molecules may be relevant to a number of human disorders such as inflammatory disease, organ failure, atherosclerosis, cardiac injury, infertility, birth defects, premature aging, AIDS, cancer, diabetic complications and mutations in general. Given that oxygen free radicals and antioxidants appear to play important roles in a number of disease processes, the identification of new reductase proteins and reductase-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research, as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PRO233.

The PRO223 polypeptides of the present invention which exhibit serine carboxypeptidease activity may be employed in vivo for therapeutic purposes as well as for in vitro purposes. Those of ordinary skill in the art will well know how to employ PRO223 polypeptides for such uses.

PRO235 polypeptides and portions thereof which may be involved in cell adhesion are also useful for in vivo therapeutic purposes, as well as for various in vitro applications. In addition, PRO235 polypeptides and portions thereof may have therapeutic applications in disease states which involve cell adhesion. Given the physiological importance of cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in cell adhesion. Therefore, peptides having homology to plexin are of particular interest to the scientific and medical communities.

Because the PRO236 and PRO262 polypeptides disclosed herein are homologous to various known β-galactosidase proteins, the PRO236 and PRO262 polypeptides disclosed herein will find use in conjugates of monoclonal antibodies and the polypeptide for specific killing of tumor cells by generation of active drug from a galactosylated prodrug (e.g., the generation of 5-fluorouridine from the prodrug β-D-galactosyl-5-fluorouridine). The PRO236 and PRO262 polypeptides disclosed herein may also find various uses both in vivo and in vitro, wherein those uses will be similar or identical to uses for which β-galactosidase proteins are now employed. Those of ordinary skill in the art will well know how to employ PRO236 and PRO262 polypeptides for such uses.

PRO239 polypeptides and portions thereof which have homology to densin may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications. In addition, PRO239 polypeptides and portions thereof may have therapeutic applications in disease states which involve synaptic mechanisms, regeneration or cell adhesion. Given the physiological importance of synaptic processes, regeneration and cell adhesion mechanisms in vivo, efforts are currently being under taken to identify new, native proteins which are involved in synaptic machinery and cell adhesion. Therefore, peptides having homology to densin are of particular interest to the scientific and medical communities.

The PRO260 polypeptides described herein can be used in assays to determine their relation to fucosidase. In particular, the PRO260 polypeptides can be used in assays in determining their ability to remove fucose or other sugar residues from proteoglycans. The PRO260 polypeptides can be assayed to determine if they have any functional or locational similarities as fucosidase. The PRO260 polypeptides can then be used to regulate the systems in which they are integral.

PRO263 can be used in assays wherein CD44 antigen is generally used to determine PRO263 activity relative to that of CD44. The results can be used accordingly.

PRO270 polypeptides and portions thereof which effect reduction-oxidation (redox) state may also be useful for in vivo therapeutic purposes, as well as for various in vitro applications. More specifically, PRO270 polypeptides may affect the expression of a large variety of genes thought to be involved in the pathogenesis of AIDS, cancer, atherosclerosis, diabetic complications and in pathological conditions involving oxidative stress such as stroke and inflammation. In addition, PRO270 polypeptides and portions thereof may affect the expression of a genes which have a role in apoptosis. Therefore, peptides having homology to thioredoxin are particularly desirable to the scientific and medical communities.

PRO272 polypeptides and portions thereof which possess the ability to bind calcium may also have numerous in vivo therapeutic uses, as well as various in vitro applications. Therefore, peptides having homology to reticulocalbin are particularly desirable. Those with ordinary skill in the art will know how to employ PRO272 polypeptides and portions thereof for such purposes.

PRO294 polypeptides and portions thereof which have homology to collagen may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel collagens and collage-like molecules may have relevance to a number of human disorders. Thus, the identification of new collagens and collage-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. Given the large number of uses for collagen, there is substantial interest in polypeptides with homology to the collagen molecule.

PRO295 polypeptides and portions thereof which have homology to integrin may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel integrins and integrin-like molecules may have relevance to a number of human disorders such as modulating the binding or activity of cells of the immune system. Thus, the identification of new integrins and integrin-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PRO295.

As the PRO293 polypeptide is clearly a leucine rich repeat polypeptide homologue, the peptide can be used in all applications that the known NLRR-1 and NLRR-2 polypeptides are used. The activity can be compared between these peptides and thus applied accordingly.

The PRO247 polypeptides described herein can be used in assays in which densin is used to determine the activity of PRO247 relative to densin or these other proteins. The results can be used accordingly in diagnostics and/or therapeutic applications with PRO247.

PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides of the present invention which possess protease activity may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO302, PRO303, PRO304, PRO307 and PRO343 polypeptides of the present invention for such purposes.

PRO328 polypeptides and portions thereof which have homology to GLIP and CRISP may also be useful for in vivo therapeutic purposes, as well as for various other applications. The identification of novel GLIP and CRISP-like molecules may have relevance to a number of human disorders which involve transcriptional regulation or are over expressed in human tumors. Thus, the identification of new GLIP and CRISP-like molecules is of special importance in that such proteins may serve as potential therapeutics for a variety of different human disorders. Such polypeptides may also play important roles in biotechnological and medical research as well as in various industrial applications. As a result, there is particular scientific and medical interest in new molecules, such as PRO328.

Uses for PRO335, PRO331 or PRO326 including uses in competitive assays with LIG-1, ALS and decorin to determine their relative activities. The results can be used accordingly. PRO335, PRO331 or PRO326 can also be used in assays where LIG-1 would be used to determine if the same effects are incurred.

PRO332 contains GAG repeat (GKEK) at amino acid positions 625-628 in FIG. 108 (SEQ ID NO:310). Slippage in such repeats can be associated with human disease. Accordingly, PRO332 can use useful for the treatment of such disease conditions by gene therapy, i.e. by introduction of a gene containing the correct GKEK sequence motif.

Other uses of PRO334 include use in assays in which fibrillin or fibulin would be used to determine the relative activity of PRO334 to fibrillin or fibulin. In particular, PRO334 can be used in assays which require the mechanisms imparted by epidermal growth factor repeats.

Native PRO346 (SEQ ID NO:320) has a Blast score of 230, corresponding to 27% homology between amino acid residues 21 to 343 with residues 35 to 1040 CGM6_HUMAN, a carcinoembryonic antigen cgm6 precursor. This homology region includes nearly all but 2 N-terminal extracellular domain residues, including an immunoglobulin superfamily homology at residues 148 to 339 of PRO346 in addition to several transmembrane residues (340-343). Carcinoembryonic antigen precursor, as explained in the Background is a tumor-specific antigen, and as such, is a recognized marker and therapeutic target for the diagnosis and treatment of colon cancer. The expression of tumor-specific antigens is often associated with the progression of neoplastic tissue disorders. Native PRO346 (SEQ ID NO:320) and P_W06874, a human carcinoembryonic antigen CEA-d have a Blast score of 224 and homology of 28% between residues 2 to 343 and 67 to 342, respectively. This homology includes the entire extracellular domain residues of native PRO346, minus the initiator methionine (residues 2 to 18) as well as several transmembrane residues (340-343).

PRO268 polypeptides which have protein disulfide isomerase activity will be useful for many applications where protein disulfide isomerase activity is desirable including, for example, for use in promoting proper disulfide bond formation in recombinantly produced proteins so as to increase the yield of correctly folded protein. Those of ordinary skill in the art will readily know how to employ such PRO268 polypeptides for such purposes.

PRO330 polypeptides of the present invention which possess biological activity related to that of the prolyl 4-hydroxylase alpha subunit protein may be employed both in vivo for therapeutic purposes and in vitro. Those of ordinary skill in the art will well know how to employ the PRO330 polypeptides of the present invention for such purposes.

Uses of the herein disclosed molecules may also be based upon the positive functional assay hits disclosed and described below.

F. Anti-PRO Antibodies

The present invention further provides anti-PRO antibodies. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.

1. Polyclonal Antibodies

The anti-PRO antibodies may comprise polyclonal antibodies. Methods of preparing polyclonal antibodies are known to the skilled artisan. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. The immunizing agent may include the PRO polypeptide or a fusion protein thereof. It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants which may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). The immunization protocol may be selected by one skilled in the art without undue experimentation.

2. Monoclonal Antibodies

The anti-PRO antibodies may, alternatively, be monoclonal antibodies. Monoclonal antibodies may be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes may be immunized in vitro.

The immunizing agent will typically include the PRO polypeptide or a fusion protein thereof Generally, either peripheral blood lymphocytes (“PBLs”) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell [Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103]. Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells may be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies [Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63].

The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against PRO. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980).

After the desired hybridoma cells are identified, the clones may be subcloned by limiting dilution procedures and grown by standard methods [Goding, supra]. Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells may be grown in vivo as ascites in a mammal.

The monoclonal antibodies secreted by the subclones may be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

The monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also may be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences [U.S. Pat. No. 4,816,567; Morrison et al., supra] or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

The antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent crosslinking.

In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly, Fab fragments, can be accomplished using routine techniques known in the art.

3. Human and Humanized Antibodies

The anti-PRO antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].

Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeye et al., Science, 239:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such “humanized” antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

Human antibodies can also be produced using various techniques known in the art, including phage display libraries [Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)]. The techniques of Cole et al. and Boerner et al. are also available for the preparation of human monoclonal antibodies (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) and Boerner et al., J. Immunol., 147(1):86-95 (1991)]. Similarly, human antibodies can be made by introducing of human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in the following scientific publications: Marks et al, Bio/Technology 10, 779-783 (1992); Lonberg et al., Nature 368 856-859 (1994); Morrison, Nature 368, 812-13 (1994); Fishwild et al., Nature Biotechnology 14, 845-51 (1996); Neuberger, Nature Biotechnology 14, 826 (1996); Lonberg and Huszar, Intern. Rev. Immunol. 13 65-93 (1995).

4. Bispecific Antibodies

Bispecific antibodies are monoclonal., preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for the PRO, the other one is for any other antigen, and preferably for a cell-surface protein or receptor or receptor. subunit.

Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities [Milstein and Cuello, Nature 305:537-539 (1983)]. Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published May 13, 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′)₂ bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)₂ fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

Fab′ fragments may be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)₂ molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

Various technique for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. U.S.A. 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (V_(H)) connected to a light-chain variable domain (V_(L)) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V_(H) and V_(L) domains of one fragment are forced to pair with the complementary V_(L) and V_(H) domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).

Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

Exemplary bispecific antibodies may bind to two different epitopes on a given PRO polypeptide herein. Alternatively, an anti-PRO polypeptide arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRRIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular PRO polypeptide. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a particular PRO polypeptide. These antibodies possess a PRO-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the PRO polypeptide and further binds tissue factor (TF).

5. Heteroconjugate Antibodies

Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Pat. No. 4,676,980], and for treatment of HV infection [WO 91/00360; WO 92/200373; EP 03089]. It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

6. Effector Function Engineering

It may be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) may be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

7. Immunoconjugates

The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPH, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y, and ¹⁸⁶Re.

Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94111026.

In another embodiment, the antibody may be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is conjugated to a cytotoxic agent (e.g., a radionucleotide).

8. Immunoliposomes

The antibodies disclosed herein may also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. U.S.A., 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. U.S.A., 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.

Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989).

9. Pharmaceutical Compositions of Antibodies

Antibodies specifically binding a PRO polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.

If the PRO polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. U.S.A., 90: 7889-7893 (1993). The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, supra.

The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and y ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S-S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

G. Uses for anti-PRO Antibodies

The anti-PRO antibodies of the invention have various utilities. For example, anti-PRO antibodies may be used in diagnostic assays for PRO, e.g., detecting its expression in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc. (1987) pp. 147-158]. The antibodies used in the diagnostic assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety may be a radioisotope, such as ³H, ¹⁴C, ³²p, ³⁵S, or ¹²⁵I, a fluorescent or chemiluminescent compound, such as fluoresein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, 144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. and Cytochem., 30:407 (1982).

Anti-PRO antibodies also are useful for the affinity purification of PRO from recombinant cell culture or natural sources. In this process, the antibodies against PRO are immobilized on a suitable support, such a Sephadex resin or filter paper, using methods well known in the art. The immobilized antibody then is contacted with a sample containing the PRO to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO from the antibody.

The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

EXAMPLES

Commercially available reagents referred to in the examples were used according to manufacturer's instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Manassas, Va.

Example 1 Extracellular Domain Homology Screening to Identify Novel Polypeptides and cDNA Encoding Therefor

The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 (Altschul, and Gish, Methods in Enzymology 266: 460-80 (1996); as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a Blast score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program “phrap” (Phil Green, University of Washington, Seattle, Wash.).

Using this extracellular domain homology screen, consensus DNA sequences were assembled relative to the other identified EST sequences. In addition, the consensus DNA sequences obtained were often (but not always) extended using repeated cycles of BLAST and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above.

Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for a PRO polypeptide. Forward (.f) and reverse (.r) PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe (.p) sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

Example 2 Isolation of cDNA Clones Encoding PRO211 and PRO217

Consensus DNA sequences were assembled as described in Example 1 above and were designated as DNA28730 and DNA28760, respectively. Based on these consensus sequences, oligonucleotides were synthesized and used to identify by PCR a cDNA library that contained the sequences of interest and for use as probes to isolate a clone of the full-length coding sequence for the PRO211 and PRO217 polypeptides. The libraries used to isolate DNA32292-1131 and DNA33094-1131 were fetal lung libraries.

cDNA clones were sequenced in their entirety. The entire nucleotide sequences of PRO211 (DNA32292-1131) and PRO217 (UNQ191) are shown in FIG. 1 (SEQ ID NO:1) and FIG. 3 (SEQ ID NO:3), respectively. The predicted polypeptides are 353 and 379 amino acid in length, respectively, with respective molecular weights of approximately 38,190 and 41,520 daltons.

The oligonucleotide sequences used in the above procedures were the following:

28730.p (OLI 516) 5′-AGGGAGCACGGACAGTGTGCAGATGTGGACGAGTGCTCACTAGCA-3′ (SEQ ID NO:5) 28730.f (OLI 517) 5′-AGAGTGTATCTCTGGCTACGC-3′ (SEQ ID NO:6) 28730.r (OLI 518) 5′-TAAGTCCGGCACATTACAGGTC-3′ (SEQ ID NO:7) 28760.p (OLI 617) 5′-CCCACGATGTATGAATGGTGGACTTTGTGTGACTCCTGGTTTCTGCATC-3′ (SEQ ID NO:8) 28760.f (OLI 618) 5′-AAAGACGCATCTGCGAGTGTCC-3′ (SEQ ID NO:9) 28760.r (OLI 619) 5′-TGCTGATTTCACACTGCTCTCCC-3′ (SEQ ID NO:10)

Example 3 Isolation of cDNA Clones Encoding Human PRO230

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA30857. An EST proprietary to Genentech was employed in the consensus assembly. The EST is designated as DNA20088 and has the nucleotide sequence shown in FIG. 7 (SEQ ID NO:13).

Based on the DNA30857 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO230.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCGAGGCCTCTGAGAAGTGGCCC-3′ (SEQ ID NO:14) reverse PCR primer 5′-GGCGGTATCTCTCTGGCCTCCC-3′ (SEQ ID NO:15)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30857 sequence which had the following nucleotide sequence

Hybridization Probe

5′-TTCTCCACAGCAGCTGTGGCATCCGATCGTGTCTCAATCCATTCTCTGGG-3′ (SEQ ID NO:16)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO230 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO230 (herein designated as DNA33223-1136 and the derived protein sequence for PRO230.

The entire nucleotide sequence of DNA33223-1136 is shown in FIG. 5 (SEQ ID NO:11). Clone DNA33223-1136 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 100-103 and ending at the stop codon at nucleotide positions 1501-1503 (FIG. 5; SEQ ID NO:11). The predicted polypeptide precursor is 467 amino acids long (FIG. 6).

Example 4 Isolation of cDNA Clones Encoding Human PRO232

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA30935. Based on the DNA30935 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO232.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGCTGTGCTACTCCTGCAAAGCCC-3′ (SEQ ID NO:19) reverse PCR primer 5′-TGCACAAGTCGGTGTCACAGCACG-3′ (SEQ ID NO:20)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30935 sequence which had the following nucleotide sequence

Hybridization Probe

5′-AGCAACGAGGACTGCCTGCAGGTGGAGAACTGCACCCAGCTGGG-3′ (SEQ ID NO:21)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO232 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO232 [herein designated as DNA34435-1140] and the derived protein sequence for PRO232.

The entire nucleotide sequence of DNA34435-1140 is shown in FIG. 8 (SEQ ID NO:17). Clone DNA34435-1140 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 17-19 and ending at the stop codon at nucleotide positions 359-361 (FIG. 8; SEQ ID NO:17). The predicted polypeptide precursor is 114 amino acids long (FIG. 9). Clone DNA34435-1140 has been deposited with ATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209250.

Analysis of the amino acid sequence of the full-length PRO232 suggests that it possesses 35% sequence identity with a stem cell surface antigen from Gallus gallus.

Example 5 Isolation of cDNA Clones Encoding PRO187

A proprietary expressed sequence tag (EST) DNA database (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST (#843193) was identified which showed homology to fibroblast growth factor (FGF-8) also known as androgen-induced growth factor. mRNA was isolated from human fetal lung tissue using reagents and protocols from Invitrogen, San Diego, Calif. (Fast Track 2). The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents (e.g., Invitrogen, San Diego, Calif., Life Technologies, Gaithersburg, Md.). The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into the cloning vector pRK5D using reagents and protocols from Life Technologies, Gaithersburg, Md. (Super Script Plasmid System). The double-stranded cDNA was sized to greater than 1000 bp and the SalI/NotI Tinkered cDNA was cloned into XhoI/NotI cleaved vector. pRK5D is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloning sites.

Several libraries from various tissue sources were screened by PCR amplification with the following oligonucleotide probes:

IN843193.f (OLI315) 5′-CAGTACGTGAGGGACCAGGGCGCCATGA-3′ (SEQ ID NO:24) IN843193.r (OLI317) 5′-CCGGTGACCTGCACGTGCTTGCCA-3′ (SEQ ID NO:25)

A positive library was then used to isolate clones encoding the PRO187 gene using one of the above oligonucleotides and the following oligonucleotide probe:

IN843193.p (OLI 316)(SEQ ID NO:26)

5′-GCGGATCTGCCGCCTGCTCANCTGGTCGGTCATGGCGCCCT-3′

A cDNA clone was sequenced in entirety. The entire nucleotide sequence of PRO187 (DNA27864-1155) is shown in FIG. 10 (SEQ ID NO:22). Clone DNA27864-1155 contains a single open reading frame with an apparent translational initiation site at nucleotide position 1 (FIG. 10; SEQ ID NO:22). The predicted polypeptide precursor is 205 amino acids long. Clone DNA27864-1155 has been deposited with the ATCC (designation: DNA27864-1155) and is assigned ATCC deposit no. ATCC 209375.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGN computer program) of the full-length sequence, the PRO187 polypeptide shows 74% amino acid sequence identity (Blast score 310) to human fibroblast growth factor-8 (androgen-induced growth factor).

Example 6 Isolation of cDNA Clones Encoding PRO265

A consensus DNA sequence was assembled relative to other EST sequences as described in Example 1 above using phrap. This consensus sequence is herein designated DNA33679. Based on the DNA33679 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO265.

PCR primers (two forward and one reverse) were synthesized:

forward PCR primer A: 5′-CGGTCTACCTGTATGGCAACC-3′ (SEQ ID NO:29); forward PCR primer B: 5′-GCAGGACAACCAGATAAACCAC-3′ (SEQ ID NO:30); reverse PCR primer 5′-ACGCAGATTTGAGAAGGCTGTC-3′ (SEQ ID NO:31)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA33679 sequence which had the following nucleotide sequence

Hybridization Probe

5′-TTCACGGGCTGCTCTTGCCCAGCTCTTGAAGCTTGAAGAGCTGCAC-3′ (SEQ ID NO:32)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO265 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human a fetal brain library.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO265 [herein designated as DNA36350-1158] (SEQ ID NO:27) and the derived protein sequence for PRO265.

The entire nucleotide sequence of DNA36350-1158 is shown in FIG. 12 (SEQ ID NO:27). Clone DNA36350-1158 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 352-354 and ending at the stop codon at positions 2332-2334 (FIG. 12). The predicted polypeptide precursor is 660 amino acids long (FIG. 13). Clone DNA36350-1158 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209378.

Analysis of the amino acid sequence of the full-length PRO265 polypeptide suggests that portions of it possess significant homology to the fibromodulin and the fibromodulin precursor, thereby indicating that PRO265 may be a novel member of the leucine rich repeat family, particularly related to fibromodulin.

Example 7 Isolation of cDNA Clones Encoding Human PRO219

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA28729. Based on the DNA28729 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO219.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTGACCCTGGTTGTGAATACTCC-3′ (SEQ ID NO:35) reverse PCR primer 5′-ACAGCCATGGTCTATAGCTTGG-3′ (SEQ ID NO:36)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28729 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GCCTGTCAGTGTCCTGAGGGACACGTGCTCCGCAGCGATGGGAAG-3′ (SEQ ID NO:37)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO219 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO219 [herein designated as DNA32290-1164] (SEQ ID NO:33) and the derived protein sequence for PRO219.

The entire nucleotide sequence of DNA32290-1164 is shown in FIG. 14 (SEQ ID NO:33). Clone DNA32290-1164 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 204-206 and ending at the stop codon at nucleotide positions 2949-2951 (FIG. 14). The predicted polypeptide precursor is 915 amino acids long (FIG. 15). Clone DNA32290-1164 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209384.

Analysis of the amino acid sequence of the full-length PRO219 polypeptide suggests that portions of it possess significant homology to the mouse and human matrilin-2 precursor polypeptides.

Example 8 Isolation of cDNA Clones Encoding Human PRO246

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA30955. Based on the DNA30955 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO246.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGGGTCTCCAGGAGAAAGACTC-3′ (SEQ ID NO:40) reverse PCR primer 5′-ATTGTGGGCCTTGCAGACATAGAC-3′ (SEQ ID NO:41)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30955 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGCCACAGCATCAAAACCTTAGAACTCAATGTACTGGTTCCTCCAGCTCC-3′ (SEQ ID NO:42)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO246 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO246 [herein designated as DNA35639-1172] (SEQ ID NO:38) and the derived protein sequence for PRO246.

The entire nucleotide sequence of DNA35639-1172 is shown in FIG. 16 (SEQ ID NO:38). Clone DNA35639-1172 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 126-128 and ending at the stop codon at nucleotide positions 1296-1298 (FIG. 16). The predicted polypeptide precursor is 390 amino acids long (FIG. 17). Clone DNA35639-1172 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209396.

Analysis of the amino acid sequence of the full-length PRO246 polypeptide suggests that it possess significant homology to the human cell surface protein HCAR, thereby indicating that PRO246 may be a novel cell surface virus receptor.

Example 9 Isolation of cDNA Clones Encoding Human PRO228

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA28758. An EST proprietary to Genentech was employed in the consensus assembly. This EST is shown in FIG. 20 (SEQ ID NO:50) and is herein designated as DNA21951.

Based on the DNA28758 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO228.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGTAATGAGCTCCATTACAG-3′ (SEQ ID NO:51) forward PCR primer 5′-GGAGTAGAAAGCGCATGG-3′ (SEQ ID NO:52) forward PCR primer 5′-CACCTGATACCATGAATGGCAG-3′ (SEQ ID NO:53) reverse PCR primer 5′-CGAGCTCGAATTAATTCG-3′ (SEQ ID NO:54) reverse PCR primer 5′-GGATCTCCTGAGCTCAGG-3′ (SEQ ID NO:55) reverse PCR primer 5′-CCTAGTTGAGTGATCCTTGTAAG-3′ (SEQ ID NO:56)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28758 sequence which had the following nucleotide sequence

Hybridization Probe

5′-ATGAGACCCACACCTCATGCCGCTGTAATCACCTGACACATTTTGCAATT-3′ (SEQ ID NO:57)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO228 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO228 [herein designated as DNA33092-1202] (SEQ ID NO:48) and the derived protein sequence for PRO228.

The entire nucleotide sequence of DNA33092-1202 is shown in FIG. 18 (SEQ ID NO:48). Clone DNA33092-1202 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 24-26 of SEQ ID NO:48 and ending at the stop codon after nucleotide position 2093 of SEQ ID NO:48. The predicted polypeptide precursor is 690 amino acids long (FIG. 19). Clone DNA33092-1202 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209420.

Analysis of the amino acid sequence of the full-length PRO228 polypeptide suggests that portions of it possess significant homology to the secretin-related proteins CD97 and EMR1 as well as the secretin member, latrophilin, thereby indicating that PRO228 may be a new member of the secretin related proteins.

Example 10 Isolation of cDNA Clones Encoding Human PRO533

The EST sequence accession number AF007268, a murine fibroblast growth factor (FGF-15) was used to search various public EST databases (e.g., GenBank, Dayhoff, etc.) The search was performed using the computer program BLAST or BLAST2 as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. The search resulted in a hit with GenBank EST AA220994, which has been identified as stratagene NT2 neuronal precursor 937230.

Based on the Genbank EST AA220994 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence. Forward and reverse PCR primers may range from 20 to 30 nucleotides (typically about 24), and are designed to give a PCR product of 100-1000 bp in length. The probe sequences are typically 40-55 bp (typically about 50) in length. In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the PCR primers.

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified below. A positive library was then used to isolate clones encoding the PRO533 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal retina. The cDNA libraries used to isolated the cDNA clones were constructed by standard methods using commercially available reagents (e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in its entirety. The full length nucleotide sequence of PRO533 is shown in FIG. 21 (SEQ ID NO:58). Clone DNA49435-1219 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 459-461 (FIG. 21; SEQ ID NO:58). The predicted polypeptide precursor is 216 amino acids long. Clone DNA47412-1219 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209480.

Based on a BLAST-2 and FastA sequence alignment analysis of the full-length sequence, PRO533 shows amino acid sequence identity to fibroblast growth factor (53%).

The oligonucleotide sequences used in the above procedure were the following:

FGF15.forward: 5′-ATCCGCCCAGATGGCTACAATGTGTA-3′ (SEQ ID NO:60); FGF15.probe: 5′-GCCTCCCGGTCTCCCTGAGCAGTGCCAAACAGCGGCAGTGTA-3′ (SEQ ID NO:61); FGF15.reverse: 5′-CCAGTCCGGTGACAAGCCCAAA-3′ (SEQ ID NO:62).

Example 11 Isolation of cDNA Clones Encoding Human PRO245

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA30954.

Based on the DNA30954 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO245.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCGTTGTGAAGTTAGTGCCCC-3′ (SEQ ID NO:65) reverse PCR primer 5′-ACCTGCGATATCCAACAGAATTG-3′ (SEQ ID NO:66)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30954 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGAAGAGGATACAGTCACTCTGGAAGTATTAGTGGCTCCAGCAGTTCC-3′ (SEQ ID NO:67)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO245 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO245 [herein designated as DNA35638-1141] and the derived protein sequence for PRO245.

The entire nucleotide sequence of DNA35638-1141 is shown in FIG. 23 (SEQ ID NO:63). Clone DNA35638-1141 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 89-91 and ending at the stop codon at nucleotide positions 1025-1027 (FIG. 23; SEQ ID NO:63). The predicted polypeptide precursor is 312 amino acids long (FIG. 24). Clone DNA35638-1141 has been deposited with ATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209265.

Analysis of the amino acid sequence of the full-length PRO245 suggests that a portion of it possesses 60% amino acid identity with the human c-myb protein and, therefore, may be a new member of the transmembrane protein receptor tyrosine kinase family.

Example 12 Isolation of cDNA Clones Encoding Human PRO220, PRO221 and PRO227

(a) PRO220

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28749. Based on the DNA28749 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO220.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TCACCTGGAGCCTTTATTGGCC-3′ (SEQ ID NO:74) reverse PCR primer 5′-ATACCAGCTATAACCAGGCTGCG-3′ (SEQ ID NO:75)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28749 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-CAACAGTAAGTGGTTTGATGCTCTTCCAAATCTAGAGATTCTGATGATTGGG-3′ (SEQ ID NO:76).

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO220 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO220 [herein designated as DNA32298-1132 and the derived protein sequence for PRO220.

The entire nucleotide sequence of DNA32298-1132 is shown in FIG. 25 (SEQ ID NO:68). Clone DNA32298-1132 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 480-482 and ending at the stop codon at nucleotide positions 2604-2606 (FIG. 25). The predicted polypeptide precursor is 708 amino acids long (FIG. 26). Clone DNA32298-1132 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209257.

Analysis of the amino acid sequence of the full-length PRO220 shows it has homology to member of the leucine rich repeat protein superfamily, including the leucine rich repeat protein and the neuronal leucine-rich repeat protein 1.

(b) PRO221

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28756. Based on the DNA28756 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO221.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCATGTGTCTCCTCCTACAAAG-3′ (SEQ ID NO:77) reverse PCR primer 5′-GGGAATAGATGTGATCTGATTGG-3′ (SEQ ID NO:78)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28756 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-CACCTGTAGCAATGCAAATCTCAAGGAAATACCTAGAGATCTTCCTCCTG-3′ (SEQ ID NO:79)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO221 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO221 [herein designated as DNA33089-1132 and the derived protein sequence for PRO221.

The entire nucleotide sequence of DNA33089-1132 is shown in FIG. 27 (SEQ ID NO:70). Clone DNA33089-1132 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 179-181 and ending at the stop codon at nucleotide positions 956-958 (FIG. 27). The predicted polypeptide precursor is 259 amino acids long (FIG. 28). PRO221 is believed to have a transmembrane region at amino acids 206-225. Clone DNA33089-1132 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209262.

Analysis of the amino acid sequence of the full-length PRO221 shows it has homology to member of the leucine rich repeat protein superfamily, including the SLIT protein.

(c) PRO227

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28740. Based on the DNA28740 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO227.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AGCAACCGCCTGAAGCTCATCC-3′ (SEQ ID NO:80) reverse PCR primer 5′-AAGGCGCGGTGAAAGATGTAGACG-3′ (SEQ ID NO:81)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28740 sequence which had the following nucleotide sequence:

Hybridization Probe

5′GACTACATGTTTCAGGACCTGTACAACCTCAAGTCACTGGAGGTTGGCGA-3′ (SEQ ID NO:82).

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO227 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO227 [herein designated as DNA33786-1132 and the derived protein sequence for PRO227.

The entire nucleotide sequence of DNA33786-1132 is shown in FIG. 29 (SEQ ID NO:72). Clone DNA33786-1132 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 33-35 and ending at the stop codon at nucleotide positions 1893-1895 (FIG. 29). The predicted polypeptide precursor is 620 amino acids long (FIG. 30). PRO227 is believed to have a transmembrane region. Clone DNA33786-1132 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209253.

Analysis of the amino acid sequence of the full-length PRO221 shows it has homology to member of the leucine rich repeat protein superfamily, including the platelet glycoprotein V precursor and the human glycoprotein V.

Example 13 Isolation of cDNA Clones Encoding Human PRO258

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA28746.

Based on the DNA28746 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO258.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GCTAGGAATTCCACAGAAGCCC-3′ (SEQ ID NO:85) reverse PCR primer 5′-AACCTGGAATGTCACCGAGCTG-3′ (SEQ ID NO:86) reverse PCR primer 5′-CCTAGCACAGTGACGAGGGACTTGGC-3′ (SEQ ID NO:87)

Additionally, synthetic oligonucleotide hybridization probes were constructed from the consensus DNA28740 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-AAGACACAGCCACCCTAAACTGTCAGTCTTCTGGGAGCAAGCCTGCAGCC-3′ (SEQ ID NO:88) 5′-GCCCTGGCAGACGAGGGCGAGTACACCTGCTCAATCTTCACTATGCCTGT-3′ (SEQ ID NO:89)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO258 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO258 [herein designated as DNA35918-1174] (SEQ ID NO:83) and the derived protein sequence for PRO258.

The entire nucleotide sequence of DNA35918-1174 is shown in FIG. 31 (SEQ ID NO:83). Clone DNA35918-1174 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 147-149 of SEQ ID NO:83 and ending at the stop codon after nucleotide position 1340 of SEQ ID NO:83 (FIG. 31). The predicted polypeptide precursor is 398 amino acids long (FIG. 32). Clone DNA35918-1174 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209402.

Analysis of the amino acid sequence of the full-length PRO258 polypeptide suggests that portions of it possess significant homology to the CRTAM and the poliovirus receptor and have an Ig domain, thereby indicating that PRO258 is a new member of the Ig superfamily.

Example 14 Isolation of cDNA Clones Encoding Human PRO266

An expressed sequence tag database was searched for ESTs having homology to SLIT, resulting in the identification of a single EST sequence designated herein as T73996. Based on the T73996 EST sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO266.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GTTGGATCTGGGCAACAATAAC-3′ (SEQ ID NO:92) reverse PCR primer 5′-ATTGTTGTGCAGGCTGAGTTTAAG-3′ (SEQ ID NO:93)

Additionally, a synthetic oligonucleotide hybridization probe was constructed which had the following nucleotide sequence

Hybridization Probe

5′-GGTGGCTATACATGGATAGCAATTACCTGGACACGCTGTCCCGGG-3′ (SEQ ID NO:94)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO266 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO266 [herein designated as DNA37150-1178] (SEQ ID NO:90) and the derived protein sequence for PRO266.

The entire nucleotide sequence of DNA37150-1178 is shown in FIG. 33 (SEQ ID NO:90). Clone DNA37150-1178 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 167-169 and ending at the stop codon after nucleotide position 2254 of SEQ ID NO:90. The predicted polypeptide precursor is 696 amino acids long (FIG. 34). Clone DNA37150-1178 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209401.

Analysis of the amino acid sequence of the full-length PRO266 polypeptide suggests that portions of it possess significant homology to the SLIT protein, thereby indicating that PRO266 may be a novel leucine rich repeat protein.

Example 15 Isolation of cDNA Clones Encoding Human PRO269

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35705. Based on the DNA35705 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO269.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGAAGGAGATGCGATGCCACCTG-3′ (SEQ ID NO:97) forward PCR primer (.f2) 5′-TGACCAGTGGGGAAGGACAG-3′ (SEQ ID NO:98) forward PCR primer (.f3) 5′-ACAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:99) reverse PCR primer (.r1) 5′-TCAGGGACAAGTGGTGTCTCTCCC-3′ (SEQ ID NO:100) reverse PCR primer (.r2) 5′-TCAGGGAAGGAGTGTGCAGTTCTG-3′ (SEQ ID NO:101)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35705 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-ACAGCTCCCGATCTCAGTTACTTGCATCGCGGACGAAATCGGCGCTCGCT-3′ (SEQ ID NO:102)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO269 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO269 [herein designated as DNA38260-1180] (SEQ ID NO:95) and the derived protein sequence for PRO269.

The entire nucleotide sequence of DNA38260-1180 is shown in FIG. 35 (SEQ ID NO:95). Clone DNA38260-1180 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 314-316 and ending at the stop codon at nucleotide positions 1784-1786 (FIG. 35; SEQ ID NO:95). The predicted polypeptide precursor is 490 amino acids long (FIG. 36). Clone DNA38260-1180 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209397.

Analysis of the amino acid sequence of the full-length PRO269 suggests that portions of it possess significant homology to the human thrombomodulin proteins, thereby indicating that PRO269 may possess one or more thrombomodulin-like domains.

Example 16 Isolation of cDNA Clones Encoding Human PRO287

A consensus DNA sequence encoding PRO287 was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28728. Based on the DNA28728 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO287.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCGATTCATAGACCTCGAGAGT-3′ (SEQ ID NO:105) reverse PCR primer 5′-GTCAAGGAGTCCTCCACAATAC-3′ (SEQ ID NO:106)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28728 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GTGTACAATGGCCATGCCAATGGCCAGCGCATTGGCCGCTTCTGT-3′ (SEQ ID NO:107)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO287 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO287 [herein designated as DNA39969-1185, SEQ ID NO:103] and the derived protein sequence for PRO287.

The entire nucleotide sequence of DNA39969-1185 is shown in FIG. 37 (SEQ ID NO:103). Clone DNA39969-1185 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 307-309 and ending at the stop codon at nucleotide positions 1552-1554 (FIG. 37; SEQ ID NO:103). The predicted polypeptide precursor is 415 amino acids long (FIG. 38). Clone DNA39969-1185 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209400.

Analysis of the amino acid sequence of the full-length PRO287 suggests that it may possess one or more procollagen C-proteinase enhancer protein precursor or procollagen C-proteinase enhancer protein-like domains. Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO287 shows nucleic acid sequence identity to procollagen C-proteinase enhancer protein precursor and procollagen C-proteinase enhancer protein (47 and 54%, respectively).

Example 17 Isolation of cDNA Clones Encoding Human PRO214

A consensus DNA sequence was assembled using phrap as described in Example 1 above. This consensus DNA sequence is designated herein as DNA28744. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence.

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified below. A positive library was then used to isolate clones encoding the PRO214 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

A cDNA clone was sequenced in its entirety. The full length nucleotide sequence of DNA32286-1191 is shown in FIG. 39 (SEQ ID NO:108). DNA32286-1191 contains a single open reading frame with an apparent translational initiation site at nucleotide position 103 (FIG. 39; SEQ ID NO:108). The predicted polypeptide precursor is 420 amino acids long (SEQ ID NO:109).

Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO214 polypeptide shows amino acid sequence identity to HT protein and/or Fibulin (49% and 38%, respectively).

The oligonucleotide sequences used in the above procedure were the following:

28744.p (OLI555) 5′-CCTGGCTATCAGCAGGTGGGCTCCAAGTGTCTCGATGTGGATGAGTGTGA-3′ (SEQ ID NO:110) 28744.f (OLI556) 5′-ATTCTGCGTGAACACTGAGGGC-3′ (SEQ ID NO:111) 28744.r (OLI557) 5′-ATCTGCTTGTAGCCCTCGGCAC-3′ (SEQ ID NO:112)

Example 18 Isolation of cDNA Clones Encoding Human PRO317

A consensus DNA sequence was assembled using phrap as described in Example 1 above, wherein the consensus sequence is herein designated as DNA28722. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence. The forward and reverse PCR primers, respectively, synthesized for this purpose were:

5′-AGGACTGCCATAACTTGCCTG (OLI489) (SEQ ID NO:115) and 5′-ATAGGAGTTGAAGCAGCGCTGC (OLI490) (SEQ ID NO:116).

The probe synthesized for this purpose was:

5′-TGTGTGGACATAGACGAGTGCCGCTACCGCTACTGCCAGCACCGC (OL1488)(SEQ ID NO:117)

mRNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology (1989), with the PCR primer pair identified above. A positive library was then used to isolate clones containing the PRO317 gene using the probe oligonucleotide identified above and one of the PCR primers.

A cDNA clone was sequenced in its entirety. The entire nucleotide sequence of DNA33461-1199 (encoding PRO317) is shown in FIG. 41 (SEQ ID NO:113). Clone DNA33461-1199 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 68-70 (FIG. 41; SEQ ID NO:113). The predicted polypeptide precursor is 366 amino acids long. The predicted signal sequence is amino acids 1-18 of FIG. 42 (SEQ ID NO:114). There is one predicted N-linked glycosylation site at amino acid residue 160. Clone DNA33461-1199 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209367.

Based on BLAST™ and FastA™ sequence alignment analysis (using the ALIGNT™ computer program) of the full-length PRO317sequence, PRO317 shows the most amino acid sequence identity to EBAF-1 (92%). The results also demonstrate a significant homology between human PRO317 and mouse LEFTY protein. The C-terminal end of the PRO317 protein contains many conserved sequences consistent with the pattern expected of a member of the TGF- superfamily.

In situ expression analysis in human tissues performed as described below evidences that there is distinctly strong expression of the PRO317 polypeptide in pancreatic tissue.

Example 19 Isolation of cDNA clones Encoding Human PRO301

A consensus DNA sequence designated herein as DNA35936 was assembled using phrap as described in Example 1 above. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence.

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified below. A positive library was then used to isolate clones encoding the PRO301 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney.

A cDNA clone was sequenced in its entirety. The full length nucleotide sequence of native sequence PRO301 is shown in FIG. 43 (SEQ ID NO:118). Clone DNA40628-1216 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 52-54 (FIG. 43; SEQ ID NO:118). The predicted polypeptide precursor is 299 amino acids long with a predicted molecular weight of 32,583 daltons and pI of 8.29. Clone DNA40628-1216 has been deposited with ATCC and is assigned ATCC deposit No. ATCC 209432.

Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO301 shows amino acid sequence identity to A33 antigen precursor (30%) and coxsackie and adenovirus receptor protein (29%).

The oligonucleotide sequences used in the above procedure were the following:

OLI2162 (35936.f1) 5′-TCGCGGAGCTGTGTTCTGTTTCCC-3′ (SEQ ID NO:120) OLI2163 (35936.p1) 5′-TGATCGCGATGGGGACAAAGGCGCAAGCTCGAGAGGAAACTGTTGTGCCT-3′ (SEQ ID NO:121) OLI2164 (35936.f2) 5′-ACACCTGGTTCAAAGATGGG-3′ (SEQ ID NO:122) OLI2165 (35936.r1) 5′-TAGGAAGAGTTGCTGAAGGCACGG-3′ (SEQ ID NO:123) OLI2166 (35936.f3) 5′-TTGCCTTACTCAGGTGCTAC-3′ (SEQ ID NO:124) OLI2167 (35936.r2) 5′-ACTCAGCAGTGGTAGGAAAG-3′ (SEQ ID NO:125)

Example 20 Isolation of cDNA Clones Encoding Human PRO224

A consensus DNA sequence assembled relative to the other identified EST sequences as described in Example 1, wherein the consensus sequence is designated herein as DNA30845. Based on the DNA30845 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO224.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AAGTTCCAGTGCCGCACCAGTGGC-3′ (SEQ ID NO:128) reverse PCR primer 5′-TTGGTTCCACAGCCGAGCTCGTCG-3′ (SEQ ID NO:129)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30845 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GAGGAGGAGTGCAGGATTGAGCCATGTACCCAGAAAGGGCAATGCCCACC-3′ (SEQ ID NO:130)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO224 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO224 [herein designated as DNA33221-1133] and the derived protein sequence for PRO224.

The entire nucleotide sequence of DNA33221-1133 is shown in FIG. 45 (SEQ ID NO:126). Clone DNA33221-1133 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 33-35 and ending at the stop codon at nucleotide positions 879-899 (FIG. 45; SEQ ID NO:126). The start of a transmembrane region begins at nucleotide position 777. The predicted polypeptide precursor is 282 amino acids long (FIG. 46). Clone DNA33221-1133 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209263.

Analysis of the amino acid sequence of the full-length PRO224 suggests that it has homology to very low-density lipoprotein receptors, apolipoprotein E receptor and chicken oocyte receptors P95. Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO224 has amino acid identity to portions of these proteins in the range from 28% to 45%, and overall identity with these proteins in the range from 33% to 39%.

Example 21 Isolation of cDNA Clones Encoding Human PRO222

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28771. Based on the DNA28771 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO222.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-ATCTCCTATCGCTGCTTTCCCGG-3′ (SEQ ID NO:133) reverse PCR primer 5′-AGCCAGGATCGCAGTAAAACTCC-3′ (SEQ ID NO:134)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28771 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-ATTTAAACTTGATGGGTCTGCGTATCTTGAGTGCTTACAAAACCTTATCT-3′ (SEQ ID NO:135)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO222 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO222 [herein designated as DNA33107-1135] and the derived protein sequence for PRO222.

The entire nucleotide sequence of DNA33107-1135 is shown in FIG. 47 (SEQ ID NO:131). Clone DNA33107-1135 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 159-161 and ending at the stop codon at nucleotide positions 1629-1631 (FIG. 47; SEQ ID NO:131). The predicted polypeptide precursor is 490 amino acids long (FIG. 48). Clone DNA33107-1135 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209251.

Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO222 shows amino acid sequence identity to mouse complement factor h precursor (25-26%), complement receptor (27-29%), mouse complement C3b receptor type 2 long form precursor (2547%) and human hypothetical protein kiaa0247 (40%).

Example 22 Isolation of cDNA clones Encoding PRO234

A consensus DNA sequence was assembled (DNA30926) using phrap as described in Example 1 above. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence.

RNA for the construction of the cDNA libraries was isolated using standard isolation protocols, e.g., Ausubel et al., Current Protocols in Molecular Biology, from tissue or cell line sources or it was purchased from commercial sources (e.g., Clontech). The cDNA libraries used to isolate the cDNA clones were constructed by standard methods (e.g., Ausubel et al.) using commercially available reagents (e.g., Invitrogen). This library was derived from 22 week old fetal brain tissue.

A cDNA clone was sequenced in its entirety. The entire nucleotide sequence of PRO234 is shown in FIG. 49 (SEQ ID NO:136). The predicted polypeptide precursor is 382 amino acids long and has a calculated molecular weight of approximately 43.1 kDa.

The oligonucleotide sequences used in the above procedure were the following:

30926.p (OLI826) (SEQ ID NO:138): 5′-GTTCATTGAAAACCTCTTGCCATCTGATGGTGACTTCTGGATTGGGC TCA-3′ 30926.f (OLI827) (SEQ ID NO:139): 5′-AAGCCAAAGAAGCCTGCAGGAGGG-3′ 30926.r.(OLI828) (SEQ ID NO:140): 5′-CAGTCCAAGCATAAAGGTCCTGGC-3′

Example 23 Isolation of cDNA Clones Encoding Human PRO231

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence was designated herein as DNA30933. Based on the DNA30933 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO231.

Three PCR primers (two forward and one reverse) were synthesized:

forward PCR primer 1 5′-CCAACTACCAAAGCTGCTGGAGCC-3′ (SEQ ID NO:143) forward PCR primer 2 5′-GCAGCTCTATTACCACGGGAAGGA-3′ (SEQ ID NO:144) reverse PCR primer 5′-TCCTTCCCGTGGTAATAGAGCTGC-3′ (SEQ ID NO:145)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30933 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGCAGAGAACCAGAGGCCGGAGGAGACTGCCTCTTTACAGCCAGG-3′ (SEQ ID NO:146)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO231 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO231 [herein designated as DNA34434-1139] and the derived protein sequence for PRO231.

The entire nucleotide sequence of DNA34434-1139 is shown in FIG. 51 (SEQ ID NO:141). Clone DNA34434-1139 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 173-175 and ending at the stop codon at nucleotide positions 1457-1459 (FIG. 51; SEQ ID NO:141). The predicted polypeptide precursor is 428 amino acids long (FIG. 52). Clone DNA34434-1139 has been deposited with ATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209252.

Analysis of the amino acid sequence of the full-length PRO231 suggests that it possesses 30% and 31% amino acid identity with the human and rat prostatic acid phosphatase precursor proteins, respectively.

Example 24 Isolation of cDNA Clones Encoding Human PRO229

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA28762. Based on the DNA28762 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO229.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TTCAGCTCATCACCTTCACCTGCC-3′ (SEQ ID NO:149) reverse PCR primer 5′-GGCTCATACAAAATACCACTAGGG-3′ (SEQ ID NO:150)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28762 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGGCCTCCACCGCTGTGAAGGGCGGGTGGAGGTGGAACAGAAAGGCCAGT-3′ (SEQ ID NO:151)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO229 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO229 [herein designated as DNA33100-1159] (SEQ ID NO:147) and the derived protein sequence for PRO229.

The entire nucleotide sequence of DNA33100-1159 is shown in FIG. 53 (SEQ ID NO:147). Clone DNA33100-1159 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 98-100 and ending at the stop codon at nucleotide positions 1139-1141 (FIG. 53). The predicted polypeptide precursor is 347 amino acids long (FIG. 54). Clone DNA33100-1159 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209377

Analysis of the amino acid sequence of the full-length PRO229 polypeptide suggests that portions of it possess significant homology to antigen wc1.1, M130 antigen and CD6.

Example 25 Isolation of cDNA Clones Encoding Human PRO238

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described above in Example 1. This consensus sequence is herein designated DNA30908. Based on the DNA30908 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO238.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGTGCTAAACTGGTGCTCTGTGGC-3′ (SEQ ID NO:154) forward PCR primer 2 5′-CAGGGCAAGATGAGCATTCC-3′ (SEQ ID NO:155) reverse PCR primer 5′-TCATACTGTTCCATCTCGGCACGC-3′ (SEQ ID NO:156)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30908 sequence which had the following nucleotide sequence

Hybridization Probe

5′-AATGGTGGGGCCCTAGAAGAGCTCATCAGAGAACTCACCGCTTCTCATGC-3′ (SEQ ID NO:157)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO238 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO238 and the derived protein sequence for PRO238.

The entire nucleotide sequence of DNA35600-1162 is shown in FIG. 55 (SEQ ID NO:152). Clone DNA35600-1162 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 134-136 and ending prior to the stop codon at nucleotide positions 1064-1066 (FIG. 55). The predicted polypeptide precursor is 310 amino acids long (FIG. 56). Clone DNA35600-1162 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209370.

Analysis of the amino acid sequence of the full-length PRO238 polypeptide suggests that portions of it possess significant homology to reductase, particularly oxidoreductase, thereby indicating that PRO238 may be a novel reductase.

Example 26 Isolation of cDNA Clones Encoding Human PRO233

The extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases. The EST databases included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence. Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program “phrap” (Phil Green, University of Washington, Seattle, Wash.

An expressed sequence tag (EST) was identified by the EST database search and a consensus DNA sequence was assembled relative to other EST sequences using phrap. This consensus sequence is herein designated DNA30945. Based on the DNA30945 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO233.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-GGTGAAGGCAGAAATTGGAGATG-3′ (SEQ ID NO:160) reverse PCR primer 5′-ATCCCATGCATCAGCCTGTTTACC-3′ (SEQ ID NO:161)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30945 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GCTGGTGTAGTCTATACATCAGATTTGTTTGCTACACAAGATCCTCAG-3′ (SEQ ID NO:162)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO233 gene using the probe oligonucleotide.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO233 [herein designated as DNA34436-1238] (SEQ ID NO:158) and the derived protein sequence for PRO233.

The entire nucleotide sequence of DNA34436-1238 is shown in FIG. 57 (SEQ ID NO:158). Clone DNA34436-1238 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 101-103 and ending at the stop codon at nucleotide positions 1001-1003 (FIG. 57). The predicted polypeptide precursor is 300 amino acids long (FIG. 58). The full-length PRO233 protein shown in FIG. 58 has an estimated molecular weight of about 32,964 daltons and a pI of about 9.52. Clone DNA34436-1238 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209523.

Analysis of the amino acid sequence of the full-length PRO233 polypeptide suggests that portions of it possess significant homology to reductase proteins, thereby indicating that PRO233 may be a novel reductase.

Example 27 Isolation of cDNA Clones Encoding Human PRO223

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA30836. Based on the DNA30836 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO223.

PCR primer pairs (one forward and two reverse) were synthesized:

forward PCR primer 5′-TTCCATGCCACCTAAGGGAGACTC-3′ (SEQ ID NO:165) reverse PCR primer 1 5′-TGGATGAGGTGTGCAATGGCTGGC-3′ (SEQ ID NO:166) reverse PCR primer 2 5′-AGCTCTCAGAGGCTGGTCATAGGG-3′ (SEQ ID NO:167)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30836 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GTCGGCCCTTTCCCAGGACTGAACATGAAGAGTTATGCCGGCTTCCTCAC-3′ (SEQ ID NO:168)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO223 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO223 [herein designated as DNA33206-1165] (SEQ ID NO:163) and the derived protein sequence for PRO223.

The entire nucleotide sequence of DNA33206-1165 is shown in FIG. 59 (SEQ ID NO:163). Clone DNA33206-1165 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 97-99 and ending at the stop codon at nucleotide positions 1525-1527 (FIG. 59). The predicted polypeptide precursor is 476 amino acids long (FIG. 60). Clone DNA33206-1165 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209372.

Analysis of the amino acid sequence of the full-length PRO223 polypeptide suggests that it possesses significant homology to various serine carboxypeptidase proteins, thereby indicating that PRO223 may be a novel serine carboxypeptidase.

Example 28 Isolation of cDNA Clones Encoding Human PRO235

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated “DNA30927”. Based on the DNA30927 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO235.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGGAATACCGCCTCCTGCAG-3′ (SEQ ID NO:171) reverse PCR primer 5′-CTTCTGCCCTTTGGAGAAGATGGC-3′ (SEQ ID NO:172)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30927 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGACTCACTGGCCCAGGCCTTCAATATCACCAGCCAGGACGAT-3′ (SEQ ID NO:173)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO235 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO235 [herein designated as DNA35558-1167] (SEQ ID NO:169) and the derived protein sequence for PRO235.

The entire nucleotide sequence of DNA35558-1167 is shown in FIG. 61 (SEQ ID NO:169). Clone DNA35558-1167 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 667-669 and ending at the stop codon at nucleotide positions 2323-2325 (FIG. 61). The predicted polypeptide precursor is 552 amino acids long (FIG. 62). Clone DNA35558-1167 has been deposited with ATCC and is assigned ATCC deposit no. 209374.

Analysis of the amino acid sequence of the full-length PRO235 polypeptide suggests that portions of it possess significant homology to the human, mouse and Xenopus plexin protein, thereby indicating that PRO235 may be a novel plexin protein.

Example 29 Isolation of cDNA Clones Encoding Human PRO236 and Human PRO262

Consensus DNA sequences were assembled relative to other EST sequences using phrap as described in Example 1 above. These consensus sequences are herein designated DNA30901 and DNA30847. Based on the DNA30901 and DNA30847 consensus sequences, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO236 and PRO262, respectively.

Based upon the DNA30901 consensus sequence, a pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TGGCTACTCCAAGACCCTGGCATG-3′ (SEQ ID NO:178) reverse PCR primer 5′-TGGACAAATCCCCTTGCTCAGCCC-3′ (SEQ ID NO:179)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30901 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGGCTTCACCGAAGCAGTGGACCTTTATTTTGACCACCTGATGTCCAGGG-3′ (SEQ ID NO:180)

Based upon the DNA30847 consensus sequence, a pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCAGCTATGACTATGATGCACC-3′ (SEQ ID NO:181) reverse PCR primer 5′-TGGCACCCAGAATGGTGTTGGCTC-3′ (SEQ ID NO:182)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30847 sequence which had the following nucleotide sequence

Hybridization Probe

5′-CGAGATGTCATCAGCAAGTTCCAGGAAGTTCCTTTGGGACCTTTACCTCC-3′ (SEQ ID NO:183)

In order to screen several libraries for a source of full-length clones, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. Positive libraries were then used to isolate clones encoding the PRO236 and PRO262 genes using the probe oligonucleotides and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue for PRO236 and human fetal liver tissue for PRO262.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO236 [herein designated as DNA35599-1168] (SEQ ID NO:174), the derived protein sequence for PRO236, the full-length DNA sequence for PRO262 [herein designated as DNA36992-1168] (SEQ ID NO:176) and the derived protein sequence for PRO262.

The entire nucleotide sequence of DNA35599-1168 is shown in FIG. 63 (SEQ ID NO:174). Clone DNA35599-1168 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 69-71 and ending at the stop codon at nucleotide positions 1977-1979 (FIG. 63). The predicted polypeptide precursor is 636 amino acids long (FIG. 64). Clone DNA35599-1168 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209373.

The entire nucleotide sequence of DNA36992-1168 is shown in FIG. 65 (SEQ ID NO:176). Clone DNA36992-1168 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 240-242 and ending at the stop codon at nucleotide positions 2202-2204 (FIG. 65). The predicted polypeptide precursor is 654 amino acids long (FIG. 66). Clone DNA36992-1168 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209382.

Analysis of the amino acid sequence of the full-length PRO236 and PRO262 polypeptides suggests that portions of those polypeptides possess significant homology to β-galactosidase proteins derived from various sources, thereby indicating that PRO236 and PRO262 may be novel β-galactosidase homologs.

Example 30 Isolation of cDNA Clones Encoding Human PRO239

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA30909. Based on the DNA30909 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO239.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CCTCCCTCTATTACCCATGTC-3′ (SEQ ID NO:186) reverse PCR primer 5′-GACCAACTTTCTCTGGGAGTGAGG-3′ (SEQ ID NO:187)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30909 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GTCACTTTATTTCTCTAACAACAAGCTCGAATCCTTACCAGTGGCAG-3′ (SEQ ID NO:188)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO239 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO239 [herein designated as DNA34407-1169] (SEQ ID NO:184) and the derived protein sequence for PRO239.

The entire nucleotide sequence of DNA34407-1169 is shown in FIG. 67 (SEQ ID NO:184). Clone DNA34407-1169 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 72-74 and ending at the stop codon at nucleotide positions 1575-1577 (FIG. 67). The predicted polypeptide precursor is 501 amino acids long (FIG. 68). Clone DNA34407-1169 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209383.

Analysis of the amino acid sequence of the full-length PRO239 polypeptide suggests that portions of it possess significant homology to the densin protein, thereby indicating that PRO239 may be a novel molecule in the densin family.

Example 31 Isolation of cDNA Clones Encoding Human PRO257

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA28731. Based on the DNA28731 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO257.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-TCTCTATTCCAAACTGTGGCG-3′ (SEQ ID NO:191) reverse PCR primer 5′-TTTGATGACGATTCGAAGGTGG-3′ (SEQ ID NO:192)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28731 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGAAGGATCCTTCACCAGCCCCAATTACCCAAAGCCGCATCCTGAGC-3′ (SEQ ID NO:193)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO257 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO257 [herein designated as DNA35841-1173 (SEQ ID NO:189) and the derived protein sequence for PRO257.

The entire nucleotide sequence of DNA35841-1173 is shown in FIG. 69 (SEQ ID NO:189). Clone DNA35841-1173 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 964-966 and ending at the stop codon at nucleotide positions 2785-2787 (FIG. 69). The predicted polypeptide precursor is 607 amino acids long (FIG. 70). Clone DNA35841-1173 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209403.

Analysis of the amino acid sequence of the full-length PRO257 polypeptide suggests that portions of it possess significant homology to the ebnerin protein, thereby indicating that PRO257 may be a novel protein member related to the ebnerin protein.

Example 32 Isolation of cDNA Clones Encoding Human PRO260

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA30834. Based on the DNA30834 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO260.

PCR primers (forward and two reverse) were synthesized:

forward PCR primer: 5′-TGGTTTGACCAGGCCAAGTTCGG-3′ (SEQ ID NO:196); reverse PCR primer A: 5′-GGATTCATCCTCAAGGAAGAGCGG-3′ (SEQ ID NO:197); and reverse PCR primer B: 5′-AACTTGCAGCATCAGCCACTCTGC-3′ (SEQ ID NO:198)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30834 sequence which had the following nucleotide sequence:

hybridization probe:

5′-TTCCGTGCCCAGCTTCGGTAGCGAGTGGTTCTGGTGGTATTGGCA-3 (SEQ ID NO:199)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO260 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO260 [herein designated as DNA33470-1175] (SEQ ID NO:194) and the derived protein sequence for PRO260.

The entire nucleotide sequence of DNA33470-1175 is shown in FIG. 71 (SEQ ID NO:194). Clone DNA33470-1175 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 67-69 and ending at the stop codon 1468-1470 (see FIG. 71). The predicted polypeptide precursor is 467 amino acids long (FIG. 72). Clone DNA33470-1175 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209398.

Analysis of the amino acid sequence of the full-length PRO260 polypeptide suggests that portions of it possess significant homology to the alpha-1-fucosidase precursor, thereby indicating that PRO260 may be a novel fucosidase.

Example 33 Isolation of cDNA Clones Encoding Human PRO263

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA30914. Based on the DNA30914 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO263.

PCR primers (tow forward and one reverse) were synthesized:

forward PCR primer 1: 5′-GAGCTTTCCATCCAGGTGTCATGC-3′ (SEQ ID NO:202); forward PCR primer 2: 5′-GTCAGTGACAGTACCTACTCGG-3′ (SEQ ID NO:203); reverse PCR primer: 5′-TGGAGCAGGAGGAGTAGTAGTAGG-3′ (SEQ ID NO:204)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30914 sequence which had the following nucleotide sequence:

hybridization probe:

5′-AGGAGGCCTGTAGGCTGCTGGGACTAAGTTTGGCCGGCAAGGACCAAGTT-3′ (SEQ ID NO:205)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO263 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO263 [herein designated as DNA34431-1177] (SEQ ID NO:200) and the derived protein sequence for PRO263.

The entire nucleotide sequence of DNA34431-1177 is shown in FIG. 73 (SEQ ID NO:200). Clone DNA34431-1177 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 160-162 of SEQ ID NO:200 and ending at the stop codon after the nucleotide at position 1126-1128 of SEQ ID NO:200 (FIG. 73). The predicted polypeptide precursor is 322 amino acids long (FIG. 74). Clone DNA34431-1177 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209399.

Analysis of the amino acid sequence of the full-length PRO263 polypeptide suggests that portions of it possess significant homology to CD44 antigen, thereby indicating that PRO263 may be a novel cell surface adhesion molecule.

Example 34 Isolation of cDNA Clones Encoding Human PRO270

A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence was designated herein as DNA35712. Based on the DNA35712 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO270. Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCTTGGATATTCGCATGGGCCTAC-3′ (SEQ ID NO:208) forward PCR primer (.f2) 5′-TGGAGACAATATCCCTGAGG-3′ (SEQ ID NO:209) reverse PCR primer (.r1) 5′-AACAGTTGGCCACAGCATGGCAGG-3′ (SEQ ID NO:210)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35712 sequence which had the following nucleotide sequence

Hybridization Probe

5′-CCATTGATGAGGAACTAGAACGGGACAAGAGGGTCACTTGGATTGTGGAG-3′ (SEQ ID NO:211)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO270 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO270 [herein designated as DNA39510-1181] (SEQ ID NO:206) and the derived protein sequence for PRO270.

The entire nucleotide sequence of DNA39510-1181 is shown in FIG. 75 (SEQ ID NO:206). Clone DNA39510-1181 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 3-5 and ending at the stop codon at nucleotide positions 891-893 (FIG. 75; SEQ ID NO:206). The predicted polypeptide precursor is 296 amino acids long (FIG. 76). Clone DNA39510-1181 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209392.

Analysis of the amino acid sequence of the full-length PRO270 suggests that portions of it possess significant homology to the thioredoxin-protein, thereby indicating that the PRO270 protein may be a novel member of the thioredoxin family.

Example 35 Isolation of cDNA Clones Encoding Human PRO271

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35737. Based on the DNA35737 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO271.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGCTTCGCTACTGCCCTC-3′ (SEQ ID NO:214) forward PCR primer 2 5′-TTCCCTTGTGGGTTGGAG-3′ (SEQ ID NO:215) forward PCR primer 3 5′-AGGGCTGGAAGCCAGTTC-3′ (SEQ ID NO:216) reverse PCR primer 1 5′-AGCCAGTGAGGAAATGCG-3′ (SEQ ID NO:217) reverse PCR primer 2 5′-TGTCCAAAGTACACACACCTGAGG-3′ (SEQ ID NO:218)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35737 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GATGCCACGATCGCCAAGGTGGGACAGCTCTTTGCCGCCTGGAAG-3′ (SEQ ID NO:219)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO271 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO271 [herein designated as DNA39423-1182] (SEQ ID NO:212) and the derived protein sequence for PRO271.

The entire nucleotide sequence of DNA39423-1182 is shown in FIG. 77 (SEQ ID NO:212). Clone DNA39423-1182 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 101-103 and ending at the stop codon at nucleotide positions 1181-1183 (FIG. 77). The predicted polypeptide precursor is 360 amino acids long (FIG. 78). Clone DNA39423-1182 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209387.

Analysis of the amino acid sequence of the full-length PRO271 polypeptide suggests that it possess significant homology to the proteoglycan link protein, thereby indicating that PRO271 may be a link protein homolog.

Example 36 Isolation of cDNA Clones Encoding Human PRO272

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA36460. Based on the DNA36460 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO272.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-CGCAGGCCCTCATGGCCAGG-3′ (SEQ ID NO:222) forward PCR primer (.f2) 5′-GAAATCCTGGGTAATTGG-3′ (SEQ ID NO:223) reverse PCR primer 5′-GTGCGCGGTGCTCACAGCTCATC-3′ (SEQ ID NO:224)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA36460 sequence which had the following nucleotide sequence

Hybridization Probe

5′-CCCCCCTGAGCGACGCTCCCCCATGATGACGCCCACGGGAACTTC-3′ (SEQ ID NO:225)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO272 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO272 [herein designated as DNA40620-1183] (SEQ ID NO:220) and the derived protein sequence for PRO272.

The entire nucleotide sequence of DNA40620-1183 is shown in FIG. 79 (SEQ ID NO:220). Clone DNA40620-1183 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 35-37 and ending at the stop codon at nucleotide positions 1019-1021 (FIG. 79). The predicted polypeptide precursor is 328 amino acids long (FIG. 80). Clone DNA40620-1183 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209388.

Analysis of the amino acid sequence of the full-length PRO272 polypeptide suggests that portions of it possess significant homology to the human and mouse reticulocalbin proteins, respectively, thereby indicating that PRO272 may be a novel reticulocalbin protein.

Example 37 Isolation of cDNA Clones Encoding Human PRO294

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35731. Based on the DNA35731 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO294.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-TGGTCTCGCACACCGATC-3′ (SEQ ID NO:228) forward PCR primer (.f2) 5′-CTGCTGTCCACAGGGGAG-3′ (SEQ ID NO:229) forward PCR primer (.f3) 5′-CCTTGAAGCATACTGCTC-3′ (SEQ ID NO:230) forward PCR primer (.f4) 5′-GAGATAGCAATTTCCGCC-3′ (SEQ ID NO:231) reverse PCR primer (.r1) 5′-TTCCTCAAGAGGGCAGCC-3′ (SEQ ID NO:232) reverse PCR primer (.r2) 5′-CTTGGCACCAATGTCCGAGATTTC-3′ (SEQ ID NO:233)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35731 sequence which had the following nucleotide sequence

5′-GCTCTGAGGAAGGTGACGCGCGGGGCCTCCGAACCCTTGGCCTTG-3′ (SEQ ID NO:234)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO294 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO294 [herein designated as DNA40604-1187] (SEQ ID NO:226) and the derived protein sequence for PRO294.

The entire nucleotide sequence of DNA40604-1187 is shown in FIG. 81 (SEQ ID NO:226). Clone DNA40604-1187 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 396-398 and ending at the stop codon at nucleotide positions 2046-2048 (FIG. 81). The predicted polypeptide precursor is 550 amino acids long (FIG. 82). Clone DNA40604-1187 has been deposited with ATCC and is assigned ATCC deposit no. 209394.

Analysis of the amino acid sequence of the full-length PRO294 polypeptide suggests that portions of it possess significant homology to portions of various collagen proteins, thereby indicating that PRO294 may be collagen-like molecule.

Example 38 Isolation of cDNA Clones Encoding Human PRO295

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35814. Based on the DNA35814 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO295.

Forward and reverse PCR primers were synthesized:

forward PCR primer (.f1) 5′-GCAGAGCGGAGATGCAGCGGCTTG-3′ (SEQ ID NO:238) forward PCR primer (.f2) 5′-CCCAGCATGTACTGCCAG-3′ (SEQ ID NO:239) forward PCR primer (.f3) 5′-TTGGCAGCTTCATGGAGG-3′ (SEQ ID NO:240) forward PCR primer (.f4) 5′-CCTGGGCAAAAATGCAAC-3′ (SEQ ID NO:241) reverse PCR primer (.r1) 5′-CTCCAGCTCCTGGCGCACCTCCTC-3′ (SEQ ID NO:242)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35814 sequence which had the following nucleotide sequence

5′-GGCTCTCAGCTACCGCGCAGGAGCGAGGCCACCCTCAATGAGATG-3′ (SEQ ID NO:243)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO295 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO295 [herein designated as DNA38268-1188] (SEQ ID NO:235) and the derived protein sequence for PRO295.

The entire nucleotide sequence of DNA38268-1188 is shown in FIG. 83 (SEQ ID NO:235). Clone DNA38268-1188 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 153-155 and ending at the stop codon at nucleotide positions 1202-1204 (FIG. 83). The predicted polypeptide precursor is 350 amino acids long (FIG. 84). Clone DNA38268-1188 has been deposited with ATCC and is assigned ATCC deposit no. 209421.

Analysis of the amino acid sequence of the full-length PRO295 polypeptide suggests that portions of it possess significant homology to the integrin proteins, thereby indicating that PRO295 may be a novel integrin.

Example 39 Isolation of cDNA Clones Encoding Human PRO293

The extracellular domain (ECD) sequences (including the secretion signal, if any) of from about 950 known secreted proteins from the Swiss-Prot public protein database were used to search expressed sequence tag (EST) databases. The EST databases included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequence. Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program “phrap” (Phil Green, University of Washington, Seattle, Wash.

Based on an expression tag sequence designated herein as T08294 identified in the above analysis, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO293.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-AACAAGGTAAGATGCCATCCTG-3′ (SEQ ID NO:246) reverse PCR primer 5′-AAACTTGTCGATGGAGACCAGCTC-3′ (SEQ ID NO:247)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the expression sequence tag which had the following nucleotide sequence

Hybridization Probe

5′-AGGGGCTGCAAAGCCTGGAGAGCCTCTCCTTCTATGACAACCAGC-3′ (SEQ ID NO:248)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO293 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO293 [herein designated as DNA37151-1193] (SEQ ID NO:244) and the derived protein sequence for PRO293.

The entire nucleotide sequence of DNA37151-1193 is shown in FIG. 85 (SEQ ID NO:244). Clone DNA37151-1193 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 881-883 and ending at the stop codon after nucleotide position 3019 of SEQ ID NO:244, FIG. 85). The predicted polypeptide precursor is 713 amino acids long (FIG. 86). Clone DNA37151-1193 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209393.

Analysis of the amino acid sequence of the full-length PRO293 polypeptide suggests that portions of it possess significant homology to the NLRR proteins, thereby indicating that PRO293 may be a novel NLRR protein.

Example 40 Isolation of cDNA Clones Encoding Human PRO247

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA33480. Based on the DNA33480 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO247.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CAACAATGAGGGCACCAAGC-3′ (SEQ ID NO:251) reverse PCR primer 5′-GATGGCTAGGTTCTGGAGGTTCTG-3′ (SEQ ID NO:252)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA33480 expression sequence tag which had the following nucleotide sequence

Hybridization Probe

5′-CAACCTGCAGGAGATTGACCTCAAGGACAACAACCTCAAGACCATCG-3′ (SEQ ID NO:253)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO247 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO247 [herein designated as DNA35673-1201] (SEQ ID NO:249) and the derived protein sequence for PRO247.

The entire nucleotide sequence of DNA35673-1201 is shown in FIG. 89 (SEQ ID NO:249). Clone DNA35673-1201 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 80-82 of SEQ ID NO:249 and ending at the stop codon after nucleotide position 1717 of SEQ ID NO:249 (FIG. 89). The predicted polypeptide precursor is 546 amino acids long (FIG. 88). Clone DNA35673-1201 has been deposited with ATCC and is assigned ATCC deposit no. 209418.

Analysis of the amino acid sequence of the full-length PRO247 polypeptide suggests that portions of it possess significant homology to the densin molecule and KIAA0231, thereby indicating that PRO247 may be a novel leucine rich repeat protein.

Example 41 Isolation of cDNA Clones Encoding Human PRO302, PRO303, PRO304, PRO307 and PRO343

Consensus DNA sequences were assembled relative to other EST sequences using phrap as described in Example 1 above. These consensus sequences are herein designated DNA35953, DNA35955, DNA35958, DNA37160 and DNA30895. Based on the DNA35953 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO302.

PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GTCCGCAAGGATGCCTACATGTTC-3′ (SEQ ID NO:264) forward PCR primer 2 5′-GCAGAGGTGTCTAAGGTTG-3′ (SEQ ID NO:265) reverse PCR primer 5′-AGCTCTAGACCAATGCCAGCTTCC-3′ (SEQ ID NO:266)

Also, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35953 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GCCACCAACTCCTGCAAGAACTTCTCAGAACTGCCCCTGGTCATG-3′ (SEQ ID NO:267)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO302 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB228).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO302 [herein designated as DNA40370-1217] (SEQ ID NO:254) and the derived protein sequence for PRO302.

The entire nucleotide sequence of DNA40370-1217 is shown in FIG. 89 (SEQ ID NO:254). Clone DNA40370-1217 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 34-36 and ending at the stop codon at nucleotide positions 1390-1392 (FIG. 89). The predicted polypeptide precursor is 452 amino acids long (FIG. 90). Various unique aspects of the PRO302 protein are shown in FIG. 90. Clone DNA40370-1217 has been deposited with the ATCC on Nov. 21, 1997 and is assigned ATCC deposit no. ATCC 209485.

Based on the DNA35955 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO303.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-GGGGAATTCACCCTATGACATTGCC-3′ (SEQ ID NO:268) reverse PCR primer 5′-GAATGCCCTGCAAGCATCAACTGG-3′ (SEQ ID NO:269)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35955 sequence which had the following nucleotide sequence:

Hybridization Probe

5′-GCACCTGTCACCTACACTAAACACATCCAGCCCATCTGTCTCCAGGCCTC-3′ (SEQ ID NO:270)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO303 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB25).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO303 [herein designated as DNA42551-1217] (SEQ ID NO:256) and the derived protein sequence for PRO303.

The entire nucleotide sequence of DNA42551-1217 is shown in FIG. 91 (SEQ ID NO:256). Clone DNA42551-1217 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 20-22 and ending at the stop codon at nucleotide positions 962-964 (FIG. 91). The predicted polypeptide precursor is 314 amino acids long (FIG. 92). Various unique aspects of the PRO303 protein are shown in FIG. 92. Clone DNA42551-1217 has been deposited on Nov. 21, 1997 with the ATCC and is assigned ATCC deposit no. ATCC 209483.

Based on the DNA35958 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO304.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GCGGAAGGGCAGAATGGGACTCCAAG-3′ (SEQ ID NO:271) forward PCR primer 2 5′-CAGCCCTGCCACATGTGC-3′ (SEQ ID NO:272) forward PCR primer 3 5′-TACTGGGTGGTCAGCAAC-3′ (SEQ ID NO:273) reverse PCR primer 5′-GGCGAAGAGCAGGGTGAGACCCC-3′ (SEQ ID NO:274)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35958 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GCCCTCATCCTCTCTGGCAAATGCAGTTACAGCCCGGAGCCCGAC-3′ (SEQ ID NO:275)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO304 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from 22 week human fetal brain tissue (LIB153).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO304 [herein designated as DNA39520-1217] (SEQ ID NO:258) and the derived protein sequence for PRO304.

The entire nucleotide sequence of DNA39520-1217 is shown in FIG. 93 (SEQ ID NO:258). Clone DNA39520-1217 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 34-36 and ending at the stop codon at nucleotide positions 1702-1704 (FIG. 93). The predicted polypeptide precursor is 556 amino acids long (FIG. 94). Various unique aspects of the PRO304 protein are shown in FIG. 94. Clone DNA39520-1217 has been deposited with ATCC on Nov. 21, 1997 and is assigned ATCC deposit no. ATCC 209482.

Based on the DNA37160 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO307.

Pairs of PCR primers (forward and reverse) were synthesized:

forward PCR primer 1 5′-GGGCAGGGATTCCAGGGCTCC-3′ (SEQ ID NO:276) forward PCR primer 2 5′-GGCTATGACAGCAGGTTC-3′ (SEQ ID NO:277) forward PCR primer 3 5′-TGACAATGACCGACCAGG-3′ (SEQ ID NO:278) reverse PCR primer 5′-GCATCGCATTGCTGGTAGAGCAAG-3′ (SEQ ID NO:279)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA37160 sequence which had the following nucleotide sequence

Hybridization Probe

5′-TTACAGTGCCCCCTGGAAACCCACTTGGCCTGCATACCGCCTCCC-3′ (SEQ ID NO:280)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO307 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB229).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO307 [herein designated as DNA41225-1217] (SEQ ID NO:260) and the derived protein sequence for PRO307.

The entire nucleotide sequence of DNA41225-1217 is shown in FIG. 95 (SEQ ID NO:260). Clone DNA41225-1217 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 92-94 and ending at the stop codon at nucleotide positions 1241-1243 (FIG. 95). The predicted polypeptide precursor is 383 amino acids long (FIG. 96). Various unique aspects of the PRO307 protein are shown in FIG. 96. Clone DNA41225-1217 has been deposited with ATCC on Nov. 21, 1997 and is assigned ATCC deposit no. ATCC 209491.

Based on the DNA30895 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO343.

A pair of PCR primers (forward and reverse) were synthesized:

forward PCR primer 5′-CGTCTCGAGCGCTCCATACAGTTCCCTTGCCCCA-3′ (SEQ ID NO:281) reverse PCR primer 5′-TGGAGGGGGAGCGGGATGCTTGTCTGGGCGACTCCGGGGGCCCCCTCATGTGCCAGGTGGA-3′ (SEQ ID NO:282)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30895 sequence which had the following nucleotide sequence

Hybridization Probe

5′-CCCTCAGACCCTGCAGAAGCTGAAGGTTCCTATCATCGACTCGGAAGTCTGCAGCCATCT (SEQ ID NO:283) GTACTGGCGGGGAGCAGGACAGGGACCCATCACTGAGGACATGCTGTGTGCCGGCTACT-3′

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO343 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue (LIB26).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO343 [herein designated as DNA43318-1217] (SEQ ID NO:262) and the derived protein sequence for PRO343.

The entire nucleotide sequence of DNA43318-1217 is shown in FIG. 97 (SEQ ID NO:262). Clone DNA43318-1217 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 53-55 and ending at the stop codon at nucleotide positions 1004-1006 (FIG. 97). The predicted polypeptide precursor is 317 amino acids long (FIG. 98). Various unique aspects of the PRO343 protein are shown in FIG. 98. Clone DNA43318-1217 has been deposited with ATCC on Nov. 21, 1997 and is assigned ATCC deposit no. ATCC 209481.

Example 42 Isolation of cDNA Clones Encoding Human PRO328

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35615. Based on the DNA35615 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO328.

Forward and reverse PCR primers were synthesized:

forward PCR primer 5′-TCCTGCAGTTTCCTGATGC-3′ (SEQ ID NO:286) reverse PCR primer 5′-CTCATATTGCACACCAGTAATTCG-3′ (SEQ ID NO:287)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35615 sequence which had the following nucleotide sequence

Hybridization Probe

5′-ATGAGGAGAAACGTTTGATGGTGGAGCTGCACAACCTCTACCGGG-3′ (SEQ ID NO:288)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO328 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO328 [herein designated as DNA40587-1231] (SEQ ID NO:284) and the derived protein sequence for PRO328.

The entire nucleotide sequence of DNA40587-1231 is shown in FIG. 99 (SEQ ID NO:284). Clone DNA40587-1231 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 15-17 and ending at the stop codon at nucleotide positions 1404-1406 (FIG. 99). The predicted polypeptide precursor is 463 amino acids long (FIG. 100). Clone DNA40587-1231 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209438.

Analysis of the amino acid sequence of the full-length PRO328 polypeptide suggests that portions of it possess significant homology to the human glioblastoma protein and to the cysteine rich secretory protein thereby indicating that PRO328 may be a novel glioblastoma protein or cysteine rich secretory protein.

Example 43 Isolation of cDNA Clones Encoding Human PRO335, PRO331 or PRO326

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA36685. Based on the DNA36685 consensus sequence, and Incyte EST sequence no. 2228990, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO335, PRO331 or PRO326.

Forward and reverse PCR primers were synthesized for the determination of PRO335:

forward PCR primer 5′-GGAACCGAATCTCAGCTA-3′ (SEQ ID NO:295) forward PCR primer 5′-CCTAAACTGAACTGGACCA-3′ (SEQ ID NO:296) forward PCR primer 5′-GGCTGGAGACACTGAACCT-3′ (SEQ ID NO:297) forward PCR primer 5′-ACAGCTGCACAGCTCAGAACAGTG-3′ (SEQ ID NO:298) reverse PCR primer 5′-CATTCCCAGTATAAAAATTTTC-3′ (SEQ ID NO:299) reverse PCR primer 5′-GGGTCTTGGTGAATGAGG-3′ (SEQ ID NO:300) reverse PCR primer 5′-GTGCCTCTCGGTTACCACCAATGG-3′ (SEQ ID NO:301)

Additionally, a synthetic oligonucleotide hybridization probe was constructed for the determination of PRO335 which had the following nucleotide sequence

Hybridization Probe

5′-GCGGCCACTGTTGGACCGAACTGTAACCAAGGGAGAAACAGCCGTCCTAC-3′ (SEQ ID NO:302)

Forward and reverse PCR primers were synthesized for the determination of PRO331:

forward PCR primer 5′-GCCTTTGACAACCTTCAGTCACTAGTGG-3′ (SEQ ID NO:303) reverse PCR primer 5′-CCCCATGTGTCCATGACTGTTCCC-3′ (SEQ ID NO:304)

Additionally, a synthetic oligonucleotide hybridization probe was constructed for the determination of PRO331 which had the following nucleotide sequence

Hybridization Probe

5′-TACTGCCTCATGACCTCTTCACTCCCTTGCATCATCTTAGAGCGG-3′ (SEQ ID NO:305)

Forward and reverse PCR primers were synthesized for the determination of PRO326:

forward PCR primer 5′-ACTCCAAGGAAATCGGATCCGTTC-3′ (SEQ ID NO:306) reverse PCR primer 5′-TTAGCAGCTGAGGATGGGCACAAC-3′ (SEQ ID NO:307)

Additionally, a synthetic oligonucleotide hybridization probe was constructed for the determination of PRO331 which had the following nucleotide sequence

Hybridization Probe

5′-GCCTTCACTGGTTTGGATGCATTGGAGCATCTAGACCTGAGTGACAACGC-3′ (SEQ ID NO:308)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO335, PRO331 or PRO326 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (PRO335 and PRO326) and human fetal brain (PRO331).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO335, PRO331 or PRO326 [herein designated as SEQ ID NOS:289, 291 and 293, respectively; see FIGS. 101, 103 and 105, respectively], and the derived protein sequence for PRO335, PRO331 or PRO326 (see FIGS. 102, 104 and 106, respectively; SEQ ID NOS:290, 292 and 294, respectively).

The entire nucleotide sequences are shown in FIGS. 101, 103 and 105, deposited with the ATCC on Jun. 2, 1998, Nov. 7, 1997 and Nov. 21, 1997, respectively.

Analysis of the amino acid sequence of the full-length PRO335, PRO331 or PRO326 polypeptide suggests that portions of it possess significant homology to the LIG-1 protein, thereby indicating that PRO335, PRO331 and PRO326 may be a novel LIG-1-related protein.

Example 44 Isolation of cDNA clones Encoding Human PRO332

Based upon an ECD homology search performed as described in Example 1 above, a consensus DNA sequence designated herein as DNA36688 was assembled. Based on the DNA36688 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO332.

A pair of PCR primers (forward and reverse) were synthesized:

5′-GCATTGGCCGCGAGACTTTGCC-3′ (SEQ ID NO:311) 5′-GCGGCCACGGTCCTTGGAAATG-3′ (SEQ ID NO:312)

A probe was also synthesized:

5′TGGAGGAGCTCAACCTCAGCTACAACCGCATCACCAGCCCACAGG-3′ (SEQ ID NO:313)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO332 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a human fetal liver library (LIB229).

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for DNA40982-1235 and the derived protein sequence for PRO332.

The entire nucleotide sequence of DNA40982-1235 is shown in FIG. 107 (SEQ ID NO:309). Clone DNA40982-1235 contains a single open reading frame (with an apparent translational initiation site at nucleotide positions 342-344, as indicated in FIG. 107). The predicted polypeptide precursor is 642 amino acids long, and has a calculated molecular weight of 72,067 (pI: 6.60). Clone DNA40982-1235 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209433.

Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO332 shows about 30-40% amino acid sequence identity with a series of known proteoglycan sequences, including, for example, fibromodulin and fibromodulin precursor sequences of various species (FMOD_BOVIN, FMOD CHICK, FMOD_RAT, FMOD_MOUSE, FMOD_HUMAN, P_R36773), osteomodulin sequences (AB000114 1, AB007848_(—)1), decorin sequences (CFU83141_(—)1, OCU03394_(—)1, P_R42266, P_R42267, P_R42260, P_R89439) keratan sulfate proteoglycans (BTU48360_(—)1, AF022890_(—)1), corneal proteoglycan (AF022256_(—)1), and bone/cartilage proteoglycans and proteoglycane precursors (PGS1_BOVIN, PGS2_MOUSE, PGS2_HUMAN).

Example 45 Isolation of cDNA clones Encoding Human PRO334

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. Based on the consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO334.

Forward and reverse PCR primers were synthesized for the determination of PRO334:

forward PCR primer 5′-GATGGTTCCTGCTCAAGTGCCCTG-3′ (SEQ ID NO:316) reverse PCR primer 5′-TTGCACTTGTAGGACCCACGTACG-3′ (SEQ ID NO:317)

Additionally, a synthetic oligonucleotide hybridization probe was constructed for the determination of PRO334 which had the following nucleotide sequence

Hybridization Probe

5′-CTGATGGGAGGACCTGTGTAGATGTTGATGAATGTGCTACAGGAAGAGCC-3′ (SEQ ID NO:318)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO334 gene using the probe oligonucleotide and one of the PCR primers.

Human fetal kidney cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO334 [herein designated as DNA41379-1236] (SEQ ID NO:314) and the derived protein sequence for PRO334.

The entire nucleotide sequence of DNA41379-1236 (also referred to as UNQ295) is shown in FIG. 109 (SEQ ID NO:314). Clone DNA41379-1236 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 203-205 and ending at the stop codon at nucleotide positions 1730-1732 (FIG. 109). The predicted polypeptide precursor is 509 amino acids long (FIG. 110). Clone DNA41379-1236 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209488.

Analysis of the amino acid sequence of the full-length PRO334 polypeptide suggests that portions of it possess significant homology to the fibulin and fibrillin proteins, thereby indicating that PRO334 may be a novel member of the EGF protein family.

Example 46 Isolation of cDNA Clones Encoding Human PRO346

A consensus DNA sequence was identified using phrap as described in Example 1 above. Specifically, this consensus sequence is herein designated DNA38240. Based on the DNA38240 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length PRO346 coding sequence.

RNA for construction of the cDNA libraries was isolated from human fetal liver. The cDNA libraries used to isolated the cDNA clones were constructed by standard methods using commercially available reagents (e.g., Invitrogen, San Diego, Calif.; Clontech, etc.) The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

A cDNA clone was sequenced in entirety. The entire nucleotide sequence of DNA44167-1243 is shown in FIG. 111 (SEQ ID NO:319). Clone DNA44167-1243 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 64-66 (FIG. 111; SEQ ID NO:319). The predicted polypeptide precursor is 450 amino acids long. Clone DNA44167-1243 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209434 (designation DNA44167-1243).

Based on a BLAST, BLAST-2 and FastA sequence alignment analysis (using the ALIGN computer program) of the full-length sequence, PRO346 shows amino acid sequence identity to carcinoembryonic antigen (28%).

The oligonucleotide sequences used in the above procedure were the following:

OLI2691 (38240.f1) 5′-GATCCTGTCACAAAGCCAGTGGTGC-3′ (SEQ ID NO:321) OLI2693 (38240.r1) 5′-CACTGACAGGGTTCCTCACCCAGG-3′ (SEQ ID NO:322) OLI2692 (3824O.p1) 5′-CTCCCTCTGGGCTGTGGAGTATGTGGGGAACATGACCCTGACATG-3′ (SEQ ID NO:323)

Example 47 Isolation of cDNA Clones Encoding Human PRO268

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35698. Based on the DNA35698 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO268.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TGAGGTGGGCAAGCGGCGAAATG-3′ (SEQ ID NO:326) forward PCR primer 2 5′-TATGTGGATCAGGACGTGCC-3′ (SEQ ID NO:327) forward PCR primer 3 5′-TGCAGGGTTCAGTCTAGATTG-3′ (SEQ ID NO:328) reverse PCR primer 5′-TTGAAGGACAAAGGCAATCTGCCAC-3′ (SEQ ID NO:329)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA35698 sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGAGTCTTGCAGTTCCCCTGGCAGTCCTGGTGCTGTTGCTTTGGG-3′ (SEQ ID NO: 330)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO268 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO268 [herein designated as DNA39427-1179] (SEQ ID NO:324) and the derived protein sequence for PRO268.

The entire nucleotide sequence of DNA39427-1179 is shown in FIG. 113 (SEQ ID NO:324). Clone DNA39427-1179 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 13-15 and ending at the stop codon at nucleotide positions 853-855 (FIG. 113). The predicted polypeptide precursor is 280 amino acids long (FIG. 114). Clone DNA39427-1179 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209395.

Analysis of the amino acid sequence of the full-length PRO268 polypeptide suggests that it possess significant homology to protein disulfide isomerase, thereby indicating that PRO268 may be a novel protein disulfide isomerase.

Example 48 Isolation of cDNA Clones Encoding Human PRO330

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA35730. Based on the DNA35730 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO330.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-CCAGGCACAATTTCCAGA-3′ (SEQ ID NO:333) forward PCR primer 2 5′-GGACCCTTCTGTGTGCCAG-3′ (SEQ ID NO:334) reverse PCR primer 1 5′-GGTCTCAAGAACTCCTGTC-3′ (SEQ ID NO:335) reverse PCR primer 2 5′-ACACTCAGCATTGCCTGGTACTTG-3′ (SEQ ID NO:336)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGGCACATGACTGACCTGATTTATGCAGAGAAAGAGCTGGTGCAG-3′ (SEQ ID NO:337)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO330 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO330 [herein designated as DNA40603-1232] (SEQ ID NO:331) and the derived protein sequence for PRO330.

The entire nucleotide sequence of DNA40603-1232 is shown in FIG. 115 (SEQ ID NO:331). Clone DNA40603-1232 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 167-169 and ending at the stop codon at nucleotide positions 1766-1768 (FIG. 115). The predicted polypeptide precursor is 533 amino acids long (FIG. 116). Clone DNA40603-1232 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209486 on Nov. 21, 1997.

Analysis of the amino acid sequence of the full-length PRO330 polypeptide suggests that portions of it possess significant homology to the mouse prolyl 4-hydroxylase alpha subunit protein, thereby indicating that PRO330 may be a novel prolyl 4-hydroxylase alpha subunit polypeptide.

Example 49 Isolation of cDNA Clones Encoding Human PRO310

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA40553. Based on the DNA40553 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO310.

Forward and reverse PCR primers were synthesized:

forward PCR primer 1 5′-TCCCCAAGCCGTTCTAGACGCGG-3′ (SEQ ID NO:342) forward PCR primer 2 5′-CTGGTTCTTCCTTGCACG-3′ (SEQ ID NO:343) reverse PCR primer 5′-GCCCAAATGCCCTAAGGCGGTATACCCC-3′ (SEQ ID NO:344)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus sequence which had the following nucleotide sequence

Hybridization Probe

5′-GGGTGTGATGCTTGGAAGCATTTTCTGTGCTTTGATCACTATGCTAGGAC-3′(SEQ ID NO:345)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO310 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO310 [herein designated as DNA43046-1225 (SEQ ID NO:340) and the derived protein sequence for PRO310 (SEQ ID NO:341).

The entire nucleotide sequence of DNA43046-1225 is shown in FIG. 119 (SEQ ID NO:340). Clone DNA43046-1225 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 81-83 and ending at the stop codon at nucleotide positions 1035-1037 (FIG. 119). The predicted polypeptide precursor is 318 amino acids long (FIG. 120) and has a calculated molecular weight of approximately 36,382 daltons. Clone DNA43046-1225 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209484.

Analysis of the amino acid sequence of the full-length PRO310 polypeptide suggests that portions of it possess homology to C. elegans proteins and to fringe, thereby indicating that PRO310 may be involved in development.

Example 50 Isolation of cDNA clones Encoding Human PRO339

An expressed sequence tag (EST) DNA database (LIFESEQ™, Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and ESTs were identified. An assembly of Incyte clones and a consensus sequence was formed using phrap as described in Example 1 above.

Forward and reverse PCR primers were synthesized based upon the assembly-created consensus sequence:

forward PCR primer 1 5′-GGGATGCAGGTGGTGTCTCATGGGG-3′ (SEQ ID NO:346) forward PCR primer 2 5′-CCCTCATGTACCGGCTCC-3′ (SEQ ID NO:347) forward PCR primer 3 5′-GTGTGACACAGCGTGGGC-3′ (SEQ ID NO:43) forward PCR primer 4 5′-GACCGGCAGGCTTCTGCG-3′ (SEQ ID NO:44) reverse PCR primer 1 5′-CAGCAGCTTCAGCCACCAGGAGTGG-3′ (SEQ ID NO:45) reverse PCR primer 2 5′-CTGAGCCGTGGGCTGCAGTCTCGC-3′ (SEQ ID NO:46)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus sequence which had the following nucleotide sequence

Hybridization Probe

5′-CCGACTACGACTGGTTCTTCATCATGCAGGATGACACATATGTGC-3′ (SEQ ID NO:47)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO339 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

A cDNA clone was sequenced in entirety. The entire nucleotide sequence of DNA43466-1225 is shown in FIG. 117 (SEQ ID NO:338). Clone DNA43466-1225 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 333-335 and ending at the stop codon found at nucleotide positions 2649-2651 (FIG. 117; SEQ ID NO:338). The predicted polypeptide precursor is 772 amino acids long and has a calculated molecular weight of approximately 86,226 daltons. Clone DNA43466-1225 has been deposited with ATCC and is assigned ATCC deposit no. ATCC 209490.

Based on a BLAST and FastA sequence alignment analysis (using the ALIGN computer program) of the full-length sequence, PRO339 has homology to C. elegans proteins and collagen-like polymer sequences as well as to fringe, thereby indicating that PRO339 may be involved in development or tissue growth.

Example 51 Isolation of cDNA Clones Encoding Human PRO244

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. Based on this consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO244.

A pair of PCR primers (forward and reverse) were synthesized:

5′-TTCAGCTTCTGGGATGTAGGG-3′ (30923.f1) (SEQ ID NO:378) 5′-TATTCCTACCATTTCACAAATCCG-3′ (30923.r1) (SEQ ID NO:379)

A probe was also synthesized:

5′-GGAGGACTGTGCCACCATGAGAGACTCTTCAAACCCAAGGCAAAATTGG-3′ (30923.p1) (SEQ ID NO:380)

In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO244 gene using the probe oligonucleotide and one of the PCR primers.

RNA for construction of the cDNA libraries was isolated from a human fetal kidney library. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence and the derived protein sequence for PRO244.

The entire nucleotide sequence of PRO244 is shown in FIG. 121 (SEQ ID NO:376). Clone DNA35668-1171 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 106-108 (FIG. 121). The predicted polypeptide precursor is 219 amino acids long. Clone DNA35668-1171 has been deposited with ATCC (designated as DNA35663-1171) and is assigned ATCC deposit no. ATCC209371. The protein has a cytoplasmic domain (aa 1-20), a transmembrane domain (aa 21-46), and an extracellular domain (aa 47-219), with a C-lectin domain at aa 55-206.

Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO244 shows notable amino acid sequence identity to hepatic lectin gallus gallus (43%), HIC hp120-binding C-type lectin (42%), macrophage lectin 2 (HUMHML2-1, 41%), and sequence PR32188 (44%).

Example 52 Use of PRO Polypeptide-Encoding Nucleic Acid as Hybridization Probes

The following method describes use of a nucleotide sequence encoding a PRO polypeptide as a hybridization probe.

DNA comprising the coding sequence of of a PRO polypeptide of interest as disclosed herein may be employed as a probe or used as a basis from which to prepare probes to screen for homologous DNAs (such as those encoding naturally-occurring variants of the PRO polypeptide) in human tissue cDNA libraries or human tissue genomic libraries.

Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions. Hybridization of radiolabeled PRO polypeptide-encoding nucleic acid-derived probe to the filters is performed in a solution of 50% formamide, 5× SSC, 0. 1% SDS, 0. 1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2× Denhardt's solution, and 10% dextran sulfate at 42° C. for 20 hours.

Washing of the filters is performed in an aqueous solution of 01× SSC and 0.1% SDS at 42° C.

DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO polypeptide can then be identified using standard techniques known in the art.

Example 53 Expression of PRO Polypeptides in E. coli

This example illustrates preparation of an unglycosylated form of a desired PRO polypeptide by recombinant expression in E. coli.

The DNA sequence encoding the desired PRO polypeptide is initially amplified using selected PCR primers. The primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector. A variety of expression vectors may be employed. An example of a suitable vector is pBR322 (derived from E. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillin and tetracycline resistance. The vector is digested with restriction enzyme and dephosphorylated.

The PCR amplified sequences are then ligated into the vector. The vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokinase cleavage site), the specific PRO polypeptide coding region, lambda transcriptional terminator, and an argU gene.

The ligation mixture is then used to transform a selected E. coli strain using the methods described in Sambrook et al., supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing.

Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics. The overnight culture may subsequently be used to inoculate a larger scale culture. The cells are then grown to a desired optical density, during which the expression promoter is turned on.

After culturing the cells for several more hours, the cells can be harvested by centrifugation. The cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized PRO polypeptide can then be purified using a metal chelating column under conditions that allow tight binding of the protein.

PRO187, PRO317, PRO301, PRO224 and PRO238 were successfully expressed in E. coli in a poly-His tagged form, using the following procedure. The DNA encoding PRO187, PRO317, PRO301, PRO224 or PRO238 was initially amplified using selected PCR primers. The primers contained restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokinase. The PCR-amplified, poly-His tagged sequences were then ligated into an expression vector, which was used to transform an E. coli host based on strain 52 (W3110 fuhA(tonA) Ion galE rpoHts(htpRts) clpP(lacIq). Transformants were first grown in LB containing 50 mg/ml carbenicillin at 30° C. with shaking until an O.D.600 of 3-5 was reached. Cultures were then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH₄)₂SO₄, 0.71 g sodium citrate-2H2O, 1.07 g KCl, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM MPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown for approximately 20-30 hours at 30° C. with shaking. Samples were removed to verify expression by SDS-PAGE analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets were frozen until purification and refolding.

E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) was resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8 buffer. Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of 0. 1M and 0.02 M, respectively, and the solution was stirred overnight at 4° C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization. The solution was centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. The supernatant was diluted with 3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify. Depending the clarified extract was loaded onto a 5 mil Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer. The column was washed with additional buffer containing 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein was eluted with buffer containing 250 mM imidazole. Fractions containing the desired protein were pooled and stored at 4° C. Protein concentration was estimated by its absorbance at 280 nm using the calculated extinction coefficient based on its amino acid sequence.

The proteins were refolded by diluting sample slowly into freshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refolding volumes were chosen so that the final protein concentration was between 50 to 100 micrograms/ml. The refolding solution was stirred gently at 4° C. for 12-36 hours. The refolding reaction was quenched by the addition of TFA to a final concentration of 0.4% (pH of approximately 3). Before further purification of the protein, the solution was filtered through a 0.22 micron filter and acetonitrile was added to 2-10% final concentration. The refolded protein was chromatographed on a Poros R1/H reversed phase column using a mobile buffer of 0.1% TFA with elution with a gradient of acetonitrile from 10 to 80%. Aliquots of fractions with A280 absorbance were analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein were pooled. Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the reversed phase resin. Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples.

Fractions containing the desired folded PRO187, PRO317, PRO301, PRO224 and PRO238 proteins, respectively, were pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins were formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered.

Example 54 Expression of PRO Polypeptides in Mammalian Cells

This example illustrates preparation of a glycosylated form of a desired PRO polypeptide by recombinant expression in mammalian cells.

The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employed as the expression vector. Optionally, the PRO polypeptide-encoding DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the PRO polypeptide DNA using ligation methods such as described in Sambrook et al., supra. The resulting vector is called pRK5-PRO polypeptide.

In one embodiment, the selected host cells may be 293 cells. Human 293 cells (ATCC CCL 1573) are grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics. About 10 μg pRK5-PRO polypeptide DNA is mixed with about 1 μg DNA encoding the VA RNA gene [Thimmappaya et al., Cell 31:543 (1982)] and dissolved in 500 μl of 1 mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added, dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄, and a precipitate is allowed to form for 10 minutes at 25° C. The precipitate is suspended and added to the 293 cells and allowed to settle for about four hours at 37° C. The culture medium is aspirated off and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293 cells are then washed with serum free medium, fresh medium is added and the cells are incubated for about 5 days.

Approximately 24 hours after the transfections, the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine. After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 15% SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO polypeptide. The cultures containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested in selected bioassays.

In an alternative technique, PRO polypeptide may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown to maximal density in a spinner flask and 700 μg pRK5-PRO polypeptide DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours. The cells are treated with 20% glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 μg/ml bovine insulin and 0.1 μg/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed PRO polypeptide can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography.

In another embodiment, PRO polypeptides can be expressed in CHO cells. The pRK5-PRO polypeptide can be transfected into CHO cells using known reagents such as CaPO₄ or DEAE-dextran. As described above, the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as ³⁵S-methionine. After determining the presence of PRO polypeptide, the culture medium may be replaced with serum free medium. Preferably, the cultures are incubated for about 6 days, and then the conditioned medium is harvested. The medium containing the expressed PRO polypeptide can then be concentrated and purified by any selected method.

Epitope-tagged PRO polypeptide may also be expressed in host CHO cells. The PRO polypeptide may be subcloned out of the pRK5 vector. The subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector. The poly-his tagged PRO polypeptide insert can then be subcloned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones. Finally, the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression. The culture medium containing the expressed poly-His tagged PRO polypeptide can then be concentrated and purified by any selected method, such as by Ni²⁺-chelate affinity chromatography.

PRO211, PRO217, PRO230, PRO219, PRO245, PRO221, PRO258, PRO301, PRO224, PRO222, PRO234, PRO229, PRO223, PRO328 and PRO332 were successfully expressed in CHO cells by both a transient and a stable expression procedure. In addition, PRO232, PRO265, PRO246, PRO228, PRO227, PRO220, PRO266, PRO269, PRO287, PRO214, PRO231, PRO233, PRO238, PRO244, PRO235, PRO236, PRO262, PRO239, PRO257, PRO260, PRO263, PRO270, PRO271, PRO272, PRO294, PRO295, PRO293, PRO247, PRO303 and PRO268 were successfully transiently expressed in CHO cells.

Stable expression in CHO cells was performed using the following procedure. The proteins were expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins were fused to an IgG1 constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly-His tagged form.

Following PCR amplification, the respective DNAs were subcloned in a CHO expression vector using standard techniques as described in Ausubel et al., Current Protocols of Molecular Biology, Unit 3.16, John Wiley and Sons (1997). CHO expression vectors are constructed to have compatible restriction sites 5′ and 3′ of the DNA of interest to allow the convenient shuttling of cDNA's. The vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24: 9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR). DHFR expression permits selection for stable maintenance of the plasmid following transfection.

Twelve micrograms of the desired plasmid DNA were introduced into approximately 10 million CHO cells using commercially available transfection reagents Superfect® (Quiagen), Dosper® or Fugene® (Boehringer Mannheim). The cells were grown and described in Lucas et al., supra. Approximately 3×10⁻⁷ cells are frozen in an ampule for further growth and production as described below.

The ampules containing the plasmid DNA were thawed by placement into water bath and mixed by vortexing. The contents were pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes. The supernatant was aspirated and the cells were resuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5% 0.2 μm diafiltered fetal bovine serum). The cells were then aliquoted into a 100 mL spinner containing 90 mL of selective media. After 1-2 days, the cells were transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37° C. After another 2-3 days, a 250 m 500 mL and 2000 mL spinners were seeded with 3×10⁵ cells/mL. The cell media was exchanged with fresh media by centrifugation and resuspension in production medium. Although any suitable CHO media may be employed, a production medium described in U.S. Pat. No. 5,122,469, issued Jun. 16, 1992 was actually used. 3L production spinner is seeded at 1.2×10⁶ cells/mL. On day 0, the cell number pH were determined. On day 1, the spinner was sampled and sparging with filtered air was commenced. On day 2, the spinner was sampled, the temperature shifted to 33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion). Throughout the production, pH was adjusted as necessary to keep at around 7.2. After 10 days, or until viability dropped below 70%, the cell culture was harvested by centrifugtion and filtering through a 0.22 μm filter. The filtrate was either stored at 4° C. or immediately loaded onto columns for purification.

For the poly-His tagged constructs, the proteins were purified using a Ni-NTA column (Qiagen). Before purification, imidazole was added to the conditioned media to a concentration of 5 mM. The conditioned media was pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. After loading, the column was washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein was subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of were purified from the conditioned media as follows. The conditioned medium was pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column was washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5. The eluted protein was immediately neutralized by collecting 1 ml fractions into tubes containing 275 μL of 1 M Tris buffer, pH 9. The highly purified protein was subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity was assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation.

PRO211, PRO217, PRO230, PRO232, PRO187, PRO265, PRO219, PRO246, PRO228, PRO533, PRO245, PRO221, PRO227, PRO220, PRO258, PRO266, PRO269, PRO287, PRO214, PRO317, PRO301, PRO224, PRO222, PRO234, PRO231, PRO229, PRO233, PRO238, PRO223, PRO235, PRO236, PRO262, PRO239, PRO257, PRO260, PRO263, PRO270, PRO271, PRO272, PRO294, PRO295, PRO293, PRO247, PRO304, PRO302, PRO307, PRO303, PRO343, PRO328, PRO326, PRO331, PRO332, PRO334, PRO346, PRO268, PRO330, PRO310 and PRO339 were also successfully transiently expressed in COS cells.

Example 55 Expression of PRO Polypeptides in Yeast

The following method describes recombinant expression of a desired PRO polypeptide in yeast.

First, yeast expression vectors are constructed for intracellular production or secretion of PRO polypeptides from the ADH2/GAPDH promoter. DNA encoding a desired PRO polypeptide, a selected signal peptide and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of the PRO polypeptide. For secretion, DNA encoding the PRO polypeptide can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, the yeast alpha-factor secretory signal/leader sequence, and linker sequences (if needed) for expression of the PRO polypeptide.

Yeast cells, such as yeast strain AB110, can then be transformed with the expression plasmids described above and cultured in selected fermentation media. The transformed yeast supernatants can be analyzed by precipitation with 10% trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

Recombinant PRO polypeptide can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters. The concentrate containing the PRO polypeptide may further be purified using selected column chromatography resins.

Example 56 Expression of PRO Polypeptides in Baculovirus-Infected Insect Cells

The following method describes recombinant expression of PRO polypeptides in Baculovirus-infected insect cells.

The desired PRO polypeptide is fused upstream of an epitope tag contained with a baculovirus expression vector. Such epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG). A variety of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen). Briefly, the PRO polypeptide or the desired portion of the PRO polypeptide (such as the sequence encoding the extracellular domain of a transmembrane protein) is amplified by PCR with primers complementary to the 5′ and 3′ regions. The 5′ primer may incorporate flanking (selected) restriction enzyme sites. The product is then digested with those selected restriction enzymes and subcloned into the expression vector.

Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGold™ virus DNA (Pharmingen) into Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL). After 4-5 days of incubation at 28° C., the released viruses are harvested and used for further amplifications. Viral infection and protein expression is performed as described by O'Reilley et al., Baculovirus expression vectors: A laboratory Manual, Oxford: Oxford University Press (1994).

Expressed poly-his tagged PRO polypeptide can then be purified, for example, by Ni²⁺-chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl₂; 0.1 mM EDTA; 10% Glycerol; 0.1% NP40; 0.4 M KCl), and sonicated twice for 20 seconds on ice. The sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10% Glycerol, pH 7.8) and filtered through a 0.45 μm filter. A Ni²⁺-NTA agarose column (commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer. The filtered cell extract is loaded onto the column at 0.5 mL per minute. The column is washed to baseline A₂₈₀ with loading buffer, at which point fraction collection is started. Next, the column is washed with a secondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% Glycerol, pH 6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀ baseline again, the column is developed with a 0 to 500 mM Imidazole gradient in the secondary wash buffer. One mL fractions are collected and analyzed by SDS-PAGE and silver staining or western blot with Ni²⁺-NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted His₁₀-tagged PRO polypeptide are pooled and dialyzed against loading buffer.

Alternatively, purification of the IgG tagged (or Fc tagged) PRO polypeptide can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography. PRO211, PRO217, PRO230, PRO187, PRO265, PRO246, PRO228, PRO533, PRO245, PRO221, PRO220, PRO258, PRO266, PRO269, PRO287, PRO214, PRO301, PRO224, PRO222, PRO234, PRO231, PRO229, PRO235, PRO239, PRO257, PRO272, PRO294, PRO295, PRO328, PRO326, PRO331, PRO334, PRO346 and PRO310 were successfully expressed in baculovirus infected Sf9 or high5 insect cells. While the expression was actually performed in a 0.5-2 L scale, it can be readily scaled up for larger (e.g. 8 L) preparations. The proteins were expressed as an IgG construct (immunoadhesin), in which the protein extracellular region was fused to an IgG1 constant region sequence containing the hinge, CH2 and CH3 domains and/or in poly-His tagged forms.

Following PCR amplification, the respective coding sequences were subcloned into a baculovirus expression vector (pb.PH.IgG for IgG fusions and pb.PH.His.c for poly-His tagged proteins), and the vector and Baculogold® baculovirus DNA (Pharmingen) were co-transfected into 105 Spodoptera frugiperda (“Sf9”) cells (ATCC CRL 1711), using Lipofectin (Gibco BRL). pb.PH.IgG and pb.PH.His are modifications of the commercially available baculovirus expression vector pVL1393 (Pharmingen), with modified polylinker regions to include the His or Fc tag sequences. The cells were grown in Hink's TNM-FH medium supplemented with 10% FBS (Hyclone). Cells were incubated for 5 days at 28° C. The supernatant was harvested and subsequently used for the first viral amplification by infecting Sf9 cells in Hink's TNM-FH medium supplemented with 10% FBS at an approximate multiplicity of infection (MOI) of 10. Cells were incubated for 3 days at 28° C. The supernatant was harvested and the expression of the constructs in the baculovirus expression vector was determined by batch binding of 1 ml of supernatant to 25 mL of Ni-NTA beads (QIAGEN) for histidine tagged proteins or Protein-A Sepharose CL-4B beads (Pharmacia) for IgG tagged proteins followed by SDS-PAGE analysis comparing to a known concentration of protein standard by Coomassie blue staining.

The first viral amplification supernatant was used to infect a spinner culture (500 ml) of Sf9 cells grown in ESF-921 medium (Expression Systems LLC) at an approximate MOI of 0.1. Cells were incubated for 3 days at 28° C. The supernatant was harvested and filtered. Batch binding and SDS-PAGE analysis was repeated, as necessary, until expression of the spinner culture was confirmed.

The conditioned medium from the transfected cells (0.5 to 3 L) was harvested by centrifugation to remove the cells and filtered through 0.22 micron filters. For the poly-His tagged constructs, the protein construct were purified using a Ni-NTA column (Qiagen). Before purification, imidazole was added to the conditioned media to a concentration of 5 mM. The conditioned media were pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4° C. After loading, the column was washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein was subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at −80° C.

Immunoadhesin (Fc containing) constructs of proteins were purified from the conditioned media as follows. The conditioned media were pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column was washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5. The eluted protein was immediately neutralized by collecting 1 ml fractions into tubes containing 275 mL of 1 M Tris buffer, pH 9. The highly purified protein was subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity of the proteins was verified by SDS polyacrylamide gel (PEG) electrophoresis and N-terminal amino acid sequencing by Edman degradation.

Example 57 Preparation of Antibodies that Bind to PRO Polypeptides

This example illustrates preparation of monoclonal antibodies which can specifically bind to a PRO polypeptide.

Techniques for producing the monoclonal antibodies are known in the art and are described, for instance, in Goding, supra. Immunogens that may be employed include purified PRO polypeptide, fusion proteins containing the PRO polypeptide, and cells expressing recombinant PRO polypeptide on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation.

Mice, such as Balb/c, are immunized with the PRO polypeptide immunogen emulsified in complete Freund's adjuvant and injected subcutaneously or intraperitoneally in an amount from 1-100 micrograms. Alternatively, the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, Mont.) and injected into the animal's hind foot pads. The immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice by retro-orbital bleeding for testing in ELISA assays to detect anti-PRO polypeptide antibodies.

After a suitable antibody titer has been detected, the animals “positive” for antibodies can be injected with a final intravenous injection of PRO polypeptide. Three to four days later, the mice are sacrificed and the spleen cells are harvested. The spleen cells are then fused (using 35% polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generate hybridoma cells which can then be plated in 96 well tissue culture plates containing HAT (hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids.

The hybridoma cells will be screened in an ELISA for reactivity against the PRO polypeptide. Determination of “positive” hybridoma cells secreting the desired monoclonal antibodies against the PRO polypeptide is within the skill in the art.

The positive hybridoma cells can be injected intraperitoneally into syngeneic Balb/c mice to produce ascites containing the anti-PRO polypeptide monoclonal antibodies. Alternatively, the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed.

Example 58 Chimeric PRO Polypeptides

PRO polypeptides may be expressed as chimeric proteins with one or more additional polypeptide domains added to facilitate protein purification. Such purification facilitating domains include, but are not limited to, metal chelating peptides such as histidine-tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized immunoglobulin, and the domain utilized in the FLAGS™ extension/affinity purification system (Immunex Corp., Seattle Wash.). The inclusion of a cleavable linker sequence such as Factor XA or enterokinase (Invitrogen, San Diego Calif.) between the purification domain and the PRO polypeptide sequence may be useful to facilitate expression of DNA encoding the PRO polypeptide.

Example 59 Purification of PRO Polypeptides Using Specific Antibodies

Native or recombinant PRO polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-PRO polypeptide, mature PRO polypeptide, or pre-PRO polypeptide is purified by immunoaffinity chromatography using antibodies specific for the PRO polypeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-PRO polypeptide antibody to an activated chromatographic resin.

Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunoglobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions.

Such an immunoaffinity column is utilized in the purification of PRO polypeptide by preparing a fraction from cells containing PRO polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble PRO polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown.

A soluble PRO polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PRO polypeptide (e.g., high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/PRO polypeptide binding (e.g., a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and PRO polypeptide is collected.

Example 60 Drug Screening

This invention is particularly useful for screening compounds by using PRO polypeptides or binding fragment thereof in any of a variety of drug screening techniques. The PRO polypeptide or fragment employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between PRO polypeptide or a fragment and the agent being tested. Alternatively, one can examine the diminution in complex formation between the PRO polypeptide and its target cell or target receptors caused by the agent being tested.

Thus, the present invention provides methods of screening for drugs or any other agents which can affect a PRO polypeptide-associated disease or disorder. These methods comprise contacting such an agent with an PRO polypeptide or fragment thereof and assaying (I) for the presence of a complex between the agent and the PRO polypeptide or fragment, or (ii) for the presence of a complex between the PRO polypeptide or fragment and the cell, by methods well known in the art. In such competitive binding assays, the PRO polypeptide or fragment is typically labeled. After suitable incubation, free PRO polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO polypeptide or to interfere with the PRO polypeptide/cell complex.

Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail in WO 84/03564, published on Sep. 13, 1984. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. As applied to a PRO polypeptide, the peptide test compounds are reacted with PRO polypeptide and washed. Bound PRO polypeptide is detected by methods well known in the art. Purified PRO polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the peptide and immobilize it on the solid support.

This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO polypeptide specifically compete with a test compound for binding to PRO polypeptide or fragments thereof. In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PRO polypeptide.

Example 61 Rational Drug Design

The goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i.e., a PRO polypeptide) or of small molecules with which they interact, e.g., agonists, antagonists, or inhibitors. Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO polypeptide or which enhance or interfere with the function of the PRO polypeptide in vivo (cf., Hodgson, Bio/Technology, 9:19-21 (1991)).

In one approach, the three-dimensional structure of the PRO polypeptide, or of an PRO polypeptide-inhibitor complex, is determined by x-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the PRO polypeptide must be ascertained to elucidate the structure and to determine active site(s) of the molecule. Less often, useful information regarding the structure of the PRO polypeptide may be gained by modeling based on the structure of homologous proteins. In both cases, relevant structural information is used to design analogous PRO polypeptide-like molecules or to identify efficient inhibitors. Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801 (1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by Athauda et al., J. Biochem., 113:742-746 (1993).

It is also possible to isolate a target-specific antibody, selected by functional assay, as described above, and then to solve its crystal structure. This approach, in principle, yields a pharmacore upon which subsequent drug design can be based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original receptor. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides would then act as the pharmacore.

By virtue of the present invention, sufficient amounts of the PRO polypeptide may be made available to perform such analytical studies as X-ray crystallography. In addition, knowledge of the PRO polypeptide amino acid sequence provided herein will provide guidance to those employing computer modeling techniques in place of or in addition to x-ray crystallography.

Example 62 Diagnostic Test Using PRO317 Polypeptide-Specific Antibodies

Particular anti-PRO317 polypeptide antibodies are useful for the diagnosis of prepathologic conditions, and chronic or acute diseases such as gynecological diseases or ischemic diseases which are characterized by differences in the amount or distribution of PRO317. PRO317 has been found to be expressed in human kidney and is thus likely to be associated with abnormalities or pathologies which affect this organ. Further, since it is so closely related to EBAF-1, it is likely to affect the endometrium and other genital tissues. Further, due to library sources of certain ESTs, it appears that PRO317 may be involved as well in forming blood vessels and hence to be a modulator of angiogenesis.

Diagnostic tests for PRO317 include methods utilizing the antibody and a label to detect PRO317 in human body fluids, tissues, or extracts of such tissues. The polypeptide and antibodies of the present invention may be used with or without modification. Frequently, the polypeptide and antibodies will be labeled by joining them, either covalently or noncovalently, with a substance which provides for a detectable signal. A wide variety of labels and conjugation techniques are known and have been reported extensively in both the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent agents, chemiluminescent agents, magnetic particles, and the like. Patents teaching the use of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. Also, recombinant immunoglobulins may be produced as shown in U.S. Pat. No. 4,816,567.

A variety of protocols for measuring soluble or membrane-bound PRO317, using either polyclonal or monoclonal antibodies specific for that PRO317, are known in the art. Examples include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioreceptor assay (RRA), and fluorescent activated cell sorting (FACS). A two-site monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on PRO317 is preferred, but a competitive binding assay may be employed. These assays are described, among other places, in Maddox et al. J Exp. Med., 158:1211 (1983).

Example 63 Identification of PRO317 Receptors

Purified PRO317 is useful for characterization and purification of specific cell surface receptors and other binding molecules. Cells which respond to PRO317 by metabolic changes or other specific responses are likely to express a receptor for PRO317. Such receptors include, but are not limited to, receptors associated with and activated by tyrosine and serine/threonine kinases. See Kolodziejczyk and Hall, supra, for a review on known receptors for the TGF- superfamily. Candidate receptors for this superfamily fall into two primary groups, termed type I and type II receptors. Both types are serine/threonine kinases. Upon activation by the appropriate ligand, type I and type II receptors physically interact to form hetero-oligomers and subsequently activate intracellular signaling cascades, ultimately regulating gene transcription and expression. In addition, TGF- binds to a third receptor class, type III, a membrane-anchored proteoglycan lacking the kinase activity typical of signal transducing molecules.

PRO317 receptors or other PRO317-binding molecules may be identified by interaction with radiolabeled PRO317. Radioactive labels may be incorporated into PRO317 by various methods known in the art. A preferred embodiment is the labeling of primary amino groups in PRO317 with ¹²⁵I Bolton-Hunter reagent (Bolton and Hunter, Biochem. J., 133:529 (1973)), which has been used to label other polypeptides without concomitant loss of biological activity (Hebert et al., J. Biol. Chem., 266:18989 (1991); McColl et al, J. Immunol., 150:4550-4555 (1993)). Receptor-bearing cells are incubated with labeled PRO317. The cells are then washed to removed unbound PRO317, and receptor-bound PRO317 is quantified. The data obtained using different concentrations of PRO317 are used to calculate values for the number and affinity of receptors.

Labeled PRO317 is useful as a reagent for purification of its specific receptor. In one embodiment of affinity purification, PRO317 is covalently coupled to a chromatography column. Receptor-bearing cells are extracted, and the extract is passed over the column. The receptor binds to the column by virtue of its biological affinity for PRO317. The receptor is recovered from the column and subjected to N-terminal protein sequencing. This amino acid sequence is then used to design degenerate oligonucleotide probes for cloning the receptor gene.

In an alternative method, mRNA is obtained from receptor-bearing cells and made into a cDNA library. The library is transfected into a population of cells, and those cells expressing the receptor are selected using fluorescently labeled PRO317. The receptor is identified by recovering and sequencing recombinant DNA from highly labeled cells.

In another alternative method, antibodies are raised against the surface of receptor bearing cells, specifically monoclonal antibodies. The monoclonal antibodies are screened to identify those which inhibit the binding of labeled PRO317. These monoclonal antibodies are then used in affinity purification or expression cloning of the receptor.

Soluble receptors or other soluble binding molecules are identified in a similar manner. Labeled PRO317 is incubated with extracts or other appropriate materials derived from the uterus. After incubation, PRO317 complexes larger than the size of purified PRO317 are identified by a sizing technique such as size-exclusion chromatography or density gradient centrifugation and are purified by methods known in the art. The soluble receptors or binding protein(s) are subjected to N-terminal sequencing to obtain information sufficient for database identification, if the soluble protein is known, or for cloning, if the soluble protein is unknown.

Example 64 Determination of PRO317-Induced Cellular Response

The biological activity of PRO317 is measured, for example, by binding of an PRO317 of the invention to an PRO317 receptor. A test compound is screened as an antagonist for its ability to block binding of PRO317 to the receptor. A test compound is screened as an agonist of the PRO317 for its ability to bind an PRO317 receptor and influence the same physiological events as PRO317 using, for example, the KIRA-ELISA assay described by Sadick et al., Analytical Biochemistry, 235:207-214 (1996) in which activation of a receptor tyrosine kinase is monitored by immuno-capture of the activated receptor and quantitation of the level of ligand-induced phosphorylation. The assay may be adapted to monitor PRO317-induced receptor activation through the use of an PRO317 receptor-specific antibody to capture the activated receptor. These techniques are also applicable to other PRO polypeptides described herein.

Example 65 Use of PRO224 for Screening Compounds

PRO224 is expressed in a cell stripped of membrane proteins and capable of expressing PRO224. Low density lipoproteins having a detectable label are added to the cells and incubated for a sufficient time for endocytosis. The cells are washed. The cells are then analysed for label bound to the membrane and within the cell after cell lysis. Detection of the low density lipoproteins within the cell determines that PRO224 is within the family of low density lipoprotein receptor proteins. Members found within this family are then used for screening compounds which affect these receptors, and particularly the uptake of cholesterol via these receptors.

Example 66 Ability of PRO Polypeptides to Inhibit Vascular Endothelial Growth Factor (VEGF) Stimulated Proliferation of Endothelial Cell Growth (Assay 9)

The ability of various PRO polypeptides to inhibit VEGF stimulated proliferation of endothelial cells was tested. Polypeptides testing positive in this assay are useful for inhibiting endothelial cell growth in mammals where such an effect would be beneficial, e.g., for inhibiting tumor growth.

Specifically, bovine adrenal cortical capillary endothelial cells (ACE) (from primary culture, maximum of 12-14 passages) were plated in 96-well plates at 500 cells/well per 100 microliter. Assay media included low glucose DMEM, 10% calf serum, 2 mM glutamine, and 1×penicillin/streptomycin/fungizone. Control wells included the following: (1) no ACE cells added; (2) ACE cells alone; (3) ACE cells plus 5 ng/ml FGF; (4) ACE cells plus 3 ng/ml VEGF; (5) ACE cells plus 3 ng/ml VEGF plus 1 ng/ml TGF-beta; and (6) ACE cells plus 3 ng/ml VEGF plus 5 ng/ml LIF. The test samples, poly-his tagged PRO polypeptides (in 100 microliter volumes), were then added to the wells (at dilutions of 1%, 0.1% and 0.01%, respectively). The cell cultures were incubated for 6-7 days at 37° C./5% CO₂. After the incubation, the media in the wells was aspirated, the cells were washed 1× with PBS. An acid phosphatase reaction mixture (100 microliter; 0.1M sodium acetate, pH 5.5, 0.1% Triton X-100, 10 mM p-nitrophenyl phosphate) was then added to each well. After a 2 hour incubation at 37° C., the reaction was stopped by addition of 10 microliters 1N NaOH. Optical density (OD) was measured on a microplate reader at 405 nm.

The activity of PRO polypeptides was calculated as the percent inhibition of VEGF (3 ng/ml) stimulated proliferation (as determined by measuring acid phosphatase activity at OD 405 nm) relative to the cells without stimulation. TGF-beta was employed as an activity reference at 1 ng/ml, since TGF-beta blocks 70-90% of VEGF-stimulated ACE cell proliferation. The results are indicative of the utility of the PRO polypeptides in cancer therapy and specifically in inhibiting tumor angiogenesis. Numerical values (relative inhibition) are determined by calculating the percent inhibition of VEGF stimulated proliferation by the PRO polypeptides relative to cells without stimulation and then dividing that percentage into the percent inhibition obtained by TGF-β at 1 ng/ml which is known to block 70-90% of VEGF stimulated cell proliferation. The results are considered positive if the PRO polypeptide exhibits 30% or greater inhibition of VEGF stimulation of endothelial cell growth (relative inhibition 30% or greater).

The following polypeptides tested positive in this assay: PRO211, PRO217, PRO187, PRO219, PRO246, PRO228, PRO245, PRO221, PRO258, PRO301, PRO224, PRO272, PRO328, PRO331, PRO224, PRO328, PRO272, PRO301, PRO331 and PRO214.

Example 67 Retinal Neuron Survival (Assay 52)

This example demonstrates that certain PRO polypeptides have efficacy in enhancing the survival of retinal neuron cells and, therefore, are useful for the therapeutic treatment of retinal disorders or injuries including, for example, treating sight loss in mammals due to retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups at postnatal day 7 (mixed population: glia and retinal neuronal types) are killed by decapitation following CO₂ anesthesia and the eyes are removed under sterile conditions. The neural retina is dissected away from the pigment epithelium and other ocular tissue and then dissociated into a single cell suspension using 0.25% trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. for 7-10 minutes after which the trypsin is inactivated by adding 1 ml soybean trypsin inhibitor. The cells are plated at 100,000 cells per well in 96 well plates in DMEM/F12 supplemented with N2 and with or without the specific test PRO polypeptide. Cells for all experiments are grown at 37° C. in a water saturated atmosphere of 5% CO₂. After 2-3 days in culture, cells are stained with calcein AM then fixed using 4% paraformaldehyde and stained with DAPI for determination of total cell count. The total cells (fluorescent) are quantified at 20× objective magnification using CCD camera and NIH image software for MacIntosh. Fields in the well are chosen at random.

The effect of various concentration of PRO polypeptides are reported herein where percent survival is calculated by dividing the total number of calcein AM positive cells at 2-3 days in culture by the total number of DAPI-labeled cells at 2-3 days in culture. Anything above 30% survival is considered positive.

The following PRO polypeptides tested positive in this assay using polypeptide concentrations within the range of 0.01% to 1.0% in the assay: PRO220 and PRO346.

Example 68 Rod Photoreceptor Cell Survival (Assay 56)

This assay shows that certain polypeptides of the invention act to enhance the survival/proliferation of rod photoreceptor cells and, therefore, are useful for the therapeutic treatment of retinal disorders or injuries including, for example, treating sight loss in mammals due to retinitis pigmentosum, AMD, etc. Sprague Dawley rat pups at 7 day postnatal (mixed population: glia and retinal neuronal cell types) are killed by decapitation following CO₂ anesthesis and the eyes are removed under sterile conditions. The neural retina is dissected away form the pigment epithelium and other ocular tissue and then dissociated into a single cell suspension using 0.25% trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. for 7-10 minutes after which the trypsin is inactivated by adding 1 ml soybean trypsin inhibitor. The cells are plated at 100,000 cells per well in 96 well plates in DMEM/F12 supplemented with N₂. Cells for all experiments are grown at 37° C. in a water saturated atmosphere of 5% CO₂. After 2-3 days in culture, cells are fixed using 4% paraformaldehyde, and then stained using CellTracker Green CMFDA. Rho 4D2 (ascites or IgG 1:100), a monoclonal antibody directed towards the visual pigment rhodopsin is used to detect rod photoreceptor cells by indirect immunofluorescence. The results are calculated as % survival: total number of calcein - rhodopsin positive cells at 2-3 days in culture, divided by the total number of rhodopsin positive cells at time 2-3 days in culture. The total cells (fluorescent) are quantified at 20×objective magnification using a CCD camera and NIH image software for MacIntosh. Fields in the well are chosen at random.

The following polypeptides tested positive in this assay: PRO220 and PRO346.

Example 69 Induction of Endothelial Cell Apoptosis (Assay 73)

The ability of PRO polypeptides to induce apoptosis in endothelial cells was tested in human venous umbilical vein endothelial cells (HUVEC, Cell Systems). A positive test in the assay is indicative of the usefulness of the polypeptide in therapeutically treating tumors as well as vascular disorders where inducing apoptosis of endothelial cells would be beneficial.

The cells were plated on 96-well microtiter plates (Amersham Life Science, cytostar-T scintillating microplate, RPNQ160, sterile, tissue-culture treated, individually wrapped), in 10% serum (CSG-medium, Cell Systems), at a density of 2×10⁴ cells per well in a total volume of 100 μl. On day 2, test samples containing the PRO polypeptide were added in triplicate at dilutions of 1%, 0.33% and 0.11%. Wells without cells were used as a blank and wells with cells only were used as a negative control. As a positive control 1:3 serial dilutions of 50 μl of a 3×stock of staurosporine were used. The ability of the PRO polypeptide to induce apoptosis was determined by processing of the 96 well plates for detection of Annexin V, a member of the calcium and phospholipid binding proteins, to detect apoptosis.

0.2 ml Annexin V—Biotin stock solution (100 μg/ml) was diluted in 4.6 ml 2×Ca²⁺ binding buffer and 2.5% BSA (1:25 dilution). 50 μl of the diluted Annexin V—Biotin solution was added to each well (except controls) to a final concentration of 1.0 μg/ml. The samples were incubated for 10-15 minutes with Annexin-Biotin prior to direct addition of ³⁵S-Streptavidin. ³⁵S-Streptavidin was diluted in 2×Ca²⁺ Binding buffer, 2.5% BSA and was added to all wells at a final concentration of 3×10⁴ cpm/well. The plates were then sealed, centrifuged at 1000 rpm for 15 minutes and placed on orbital shaker for 2 hours. The analysis was performed on a 1450 Microbeta Trilux (Wallac). Percent above background represents the percentage amount of counts per minute above the negative controls. Percents greater than or equal to 30% above background are considered positive.

The following PRO polypeptides tested positive in this assay: PRO228, PRO217 and PRO301.

Example 70 PDB12 Cell Inhibition (Assay 40)

This example demonstrates that various PRO polypeptides have efficacy in inhibiting protein production by PDB12 pancreatic ductal cells and are, therefore, useful in the therapeutic treatment of disorders which involve protein secretion by the pancreas, including diabetes, and the like.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 well plates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100 μL of growth media with the PRO polypeptide test sample or negative control lacking the PRO polypeptide is then added to well, for a final volume of 200 μL. Controls contain growth medium containing a protein shown to be inactive in this assay. Cells are incubated for 4 days at 37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and the flourescent reading is measured at 4 hours post addition of AB, on a microtiter plate reader at 530 nm excitation and 590 nm emission. The standard employed is cells without Bovine Pituitary Extract (BPE) and with various concentrations of BPE. Buffer or CM controls from unknowns are run 2 times on each 96 well plate.

These assays allow one to calculate a percent decrease in protein production by comparing the Alamar Blue Dye calculated protein concentration produced by the PRO polypeptide-treated cells with the Alamar Blue Dye calculated protein concentration produced by the negative control cells. A percent decrease in protein production of greater than or equal to 25% as compared to the negative control cells is considered positive.

The following polypeptides tested positive in this assay: PRO211, PRO287, PRO301 and PRO293.

Example 71 Stimulation of Adult Heart Hypertrophy (Assay 2)

This assay is designed to measure the ability of various PRO polypeptides to stimulate hypertrophy of adult heart. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of various cardiac insufficiency disorders.

Ventricular myocytes freshly isolated from adult (250g) Sprague Dawley rats are plated at 2000 cell/well in 180 μl volume. Cells are isolated and plated on day 1, the PRO polypeptide-containing test samples or growth medium only (negative control) (20 μl volume) is added on day 2 and the cells are then fixed and stained on day 5. After staining, cell size is visualized wherein cells showing no growth enhancement as compared to control cells are given a value of 0.0, cells showing small to moderate growth enhancement as compared to control cells are given a value of 1.0 and cells showing large growth enhancement as compared to control cells are given a value of 2.0. Any degree of growth enhancement as compared to the negative control cells is considered positive for the assay.

The following PRO polypeptides tested positive in this assay: PRO287, PRO301, PRO293 and PRO303.

Example 72 PDB12 Cell Proliferation (Assay 29)

This example demonstrates that various PRO polypeptides have efficacy in inducing proliferation of PDB12 pancreatic ductal cells and are, therefore, useful in the therapeutic treatment of disorders which involve protein secretion by the pancreas, including diabetes, and the like.

PDB12 pancreatic ductal cells are plated on fibronectin coated 96 well plates at 1.5×10³ cells per well in 100 μL/180 μL of growth media. 100 μL of growth media with the PRO polypeptide test sample or negative control lacking the PRO polypeptide is then added to well, for a final volume of 200 μL. Controls contain growth medium containing a protein shown to be inactive in this assay. Cells are incubated for 4 days at 37° C. 20 μL of Alamar Blue Dye (AB) is then added to each well and the flourescent reading is measured at 4 hours post addition of AB, on a microtiter plate reader at 530 nm excitation and 590 nm emission. The standard employed is cells without Bovine Pituitary Extract (BPE) and with various concentrations of BPE. Buffer or growth medium only controls from unknowns are run 2 times on each 96 well plate.

Percent increase in protein production is calculated by comparing the Alamar Blue Dye calculated protein concentration produced by the PRO polypeptide-treated cells with the Alamar Blue Dye calculated protein concentration produced by the negative control cells. A percent increase in protein production of greater than or equal to 25% as compared to the negative control cells is considered positive.

The following PRO polypeptides tested positive in this assay: PRO301 and PRO303.

Example 73 Enhancement of Heart Neonatal Hypertrophy (Assay 1)

This assay is designed to measure the ability of PRO polypeptides to stimulate hypertrophy of neonatal heart. PRO polypeptides testing positive in this assay are expected to be useful for the therapeutic treatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats were obtained. Cells (180 μl at 7.5×10⁴/ml, serum <0.1%, freshly isolated) are added on day 1 to 96-well plates previously coated with DMEM/F12+4% FCS. Test samples containing the test PRO polypeptide or growth medium only (hegative control) (20 μl/well) are added directly to the wells on day 1. PGF (20 μl/well) is then added on day 2 at final concentration of 10⁻⁶ M. The cells are then stained on day 4 and visually scored on day 5, wherein cells showing no increase in size as compared to negative controls are scored 0.0, cells showing a small to moderate increase in size as compared to negative controls are scored 1.0 and cells showing a large increase in size as compared to negative controls are scored 2.0. A positive result in the assay is a score of 1.0 or greater.

The following polypeptides tested positive in this assay: PRO224 and PRO231.

Example 74 Stimulatory Activity in Mixed Lymphocyte Reaction (MLR) Assay (Assay 24)

This example shows that certain polypeptides of the invention are active as a stimulator of the proliferation of stimulated T-lymphocytes. Compounds which stimulate proliferation of lymphocytes are useful therapeutically where enhancement of an immune response is beneficial. A therapeutic agent may take the form of antagonists of the polypeptide of the invention, for example, murine-human chimeric, humanized or human antibodies against the polypeptide.

The basic protocol for this assay is described in Current Protocols in Immunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D H Marglies, E M Shevach, W Strober, National Insitutes of Health, Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclear cells (PBMC) are isolated from mammalian individuals, for example a human volunteer, by leukopheresis (one donor will supply stimulator PBMCs, the other donor will supply responder PBMCs). If desired, the cells are frozen in fetal bovine serum and DMSO after isolation. Frozen cells may be thawed overnight in assay media (37° C., 5% CO₂) and then washed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetal bovine serum, 1% penicillin/streptomycin, 1% glutaline, 1% HEPES, 1% non-essential amino acids, 1% pyruvate). The stimulator PBMCs are prepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgG is used as the control. The wells are then incubated at 37° C, 5% CO₂ for 4 days. On day 5, each well is pulsed with tritiated thymidine (1.0 mC/well; Amersham). After 6 hours the cells are washed 3 times and then the uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens of Balb/c mice and C57B6 mice. The cells are teased from freshly harvested spleens in assay media (RPMI; 10% fetal bovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential amino acids, 1% pyruvate) and the PBMCs are isolated by overlaying these cells over Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20 minutes, collecting and washing the mononuclear cell layer in assay media and resuspending the cells to 1×10⁷ cells/ml of assay media. The assay is then conducted as described above.

Positive increases over control are considered positive with increases of greater than or equal to 180% being preferred. However, any value greater than control indicates a stimulatory effect for the test protein.

The following PRO polypeptides tested positive in this assay: PRO245, PRO269, PRO217, PRO301, PRO266, PRO335, PRO331, PRO533 and PRO326.

Example 75 Pericyte c-Fos Induction (Assay 93)

This assay shows that certain polypeptides of the invention act to induce the expression of c-fos in pericyte cells and, therefore, are useful not only as diagnostic markers for particular types of pericyte-associated tumors but also for giving rise to antagonists which would be expected to be useful for the therapeutic treatment of pericyte-associated tumors. Specifically, on day 1, pericytes are received from VEC Technologies and all but 5 ml of media is removed from flask. On day 2, the pericytes are trypsinized, washed, spun and then plated onto 96 well plates. On day 7, the media is removed and the pericytes are treated with 100 μl of PRO polypeptide test samples and controls (positive control=DME+5% serum +/−PDGF at 500 ng/ml; negative control=protein 32). Replicates are averaged and SD/CV are determined. Fold increase over Protein 32 (buffer control) value indicated by chemiluminescence units (RLU) luminometer reading verses frequency is plotted on a histogram. Two-fold above Protein 32 value is considered positive for the assay. ASY Matrix: Growth media=low glucose DMEM=20% FBS+1×pen strep+1×fungizone. Assay Media=low glucose DMEM+5% FBS.

The following polypeptides tested positive in this assay: PRO214, PRO219, PRO221 and PRO224.

Example 76 Ability of PRO Polypeptides to Stimulate the Release of Proteoglycans from Cartilage (Assay 97)

The ability of various PRO polypeptides to stimulate the release of proteoglycans from cartilage tissue was tested as follows.

The metacarphophalangeal joint of 4-6 month old pigs was aseptically dissected, and articular cartilage was removed by free hand slicing being careful to avoid the underlying bone. The cartilage was minced and cultured in bulk for 24 hours in a humidified atmosphere of 95% air, 5% CO₂ in serum free (SF) media (DME/F121:1) woth 0.1% BSA and 100 U/ml penicillin and 100 μg/ml streptomycin. After washing three times, approximately 100 mg of articular cartilage was aliquoted into micronics tubes and incubated for an additional 24 hours in the above SF media. PRO polypeptides were then added at 1% either alone or in combination with 18 ng/ml interleukin-1α, a known stimulator of proteoglycan release from cartilage tissue. The supernatant was then harvested and assayed for the amount of proteoglycans using the 1,9-dimethyl-methylene blue (DMB) calorimetric assay (Farndale and Buttle, Biochem. Biophys. Acta 883:173-177 (1985)). A positive result in this assay indicates that the test polypeptide will find use, for example, in the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis.

When various PRO polypeptides were tested in the above assay, the polypeptides demonstrated a marked ability to stimulate release of proteoglycans from cartilage tissue both basally and after stimulation with interleukin-1α and at 24 and 72 hours after treatment, thereby indicating that these PRO polypeptides are useful for stimulating proteoglycan release from cartilage tissue. As such, these PRO polypeptides are useful for the treatment of sports-related joint problems, articular cartilage defects, osteoarthritis or rheumatoid arthritis. The polypeptides testing positive in this assay are: PRO211.

Example 77 Skin Vascular Permeability Assay (Assay 64)

This assay shows that certain polypeptides of the invention stimulate an immune response and induce inflammation by inducing mononuclear cell, eosinophil and PMN infiltration at the site of injection of the animal. Compounds which stimulate an immune response are useful therapeutically where stimulation of an immune response is beneficial. This skin vascular permeability assay is conducted as follows. Hairless guinea pigs weighing 350 grams or more are anesthetized with ketamine (75-80 mg/Kg) and 5 mg/Kg xylazine intramuscularly (IM). A sample of purified polypeptide of the invention or a conditioned media test sample is injected intradermally onto the backs of the test animals with 100 μl per injection site. It is possible to have about 10-30, preferably about 16-24, injection sites per animal. One μl of Evans blue dye (1% in physiologic buffered saline) is injected intracardially. Blemishes at the injection sites are then measured (mm diameter) at 1 hr and 6 hr post injection. Animals were sacrificed at 6 hrs after injection. Each skin injection site is biopsied and fixed in formalin. The skins are then prepared for histopathologic evaluation. Each site is evaluated for inflammatory cell infiltration into the skin. Sites with visible inflammatory cell inflammation are scored as positive. Inflammatory cells may be neutrophilic, eosinophilic, monocytic or lymphocytic. At least a minimal perivascular infiltrate at the injection site is scored as positve, no infiltrate at the site of injection is scored as negative.

The following polypeptides tested positive in this assay: PRO245, PRO217, PRO326, PRO266, PRO272, PRO301, PRO331 and PRO335.

Example 78 Enhancement of Heart Neonatal Hypertrophy Induced by F2a (Assay 37)

This assay is designed to measure the ability of PRO polypeptides to stimulate hypertrophy of neonatal heart. PRO polypeptides testing positive in this assay are expected to be useful for the therapeutic treatment of various cardiac insufficiency disorders.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats were obtained. Cells (180 μl at 7.5×10⁴/ml, serum <0.1%, freshly isolated) are added on day 1 to 96-well plates previously coated with DMEM/F12+4% FCS. Test samples containing the test PRO polypeptide (20 μl/well) are added directly to the wells on day 1. PGF (20 μl/well) is then added on day 2 at a final concentration of 10⁻⁶ M. The cells are then stain on day 4 and visually scored on day 5. Visual scores are based on cell size, wherein cells showing no increase in size as compared to negative controls are scored 0.0, cells showing a small to moderate increase in size as compared to negative controls are scored 1.0 and cells showing a large increase in size as compared to negative controls are scored 2.0. A score of 1.0 or greater is considered positive.

No PBS is included, since calcium concentration is critical for assay response. Plates are coated with DMEM/F12 plus 4% FCS (200 μl/well). Assay media included: DMEM/F12 (with 2.44 gm bicarbonate), μg/ml transferrin, 1 μg/ml insulin, 1 μg/ml aprotinin, 2 mmol/L glutamine, 100 U/ml penicillin G, 100 μg/ml streptomycin. Protein buffer containing mannitol (4%) gave a positive signal (score 3.5) at 1/10 (0.4%) and 1/100 (0.04%), but not at 1/1000 (0.004%). Therefore the test sample buffer containing mannitol is not run.

The following PRO polypeptides tested positive in this assay: PRO224.

Example 79 Inhibitory Activity in Mixed Lymphocyte Reaction (MLR) Assay (Assay 67)

This example shows that one or more of the polypeptides of the invention are active as inhibitors of the proliferation of stimulated T-lymphocytes. Compounds which inhibit proliferation of lymphocytes are useful therapeutically where suppression of an immune response is beneficial.

The basic protocol for this assay is described in Current Protocols in Immunology, unit 3.12; edited by J E Coligan, A M Kruisbeek, D H Marglies, E M Shevach, W Strober, National Insitutes of Health, Published by John Wiley & Sons, Inc.

More specifically, in one assay variant, peripheral blood mononuclear cells (PBMC) are isolated from mammalian individuals, for example a human volunteer, by leukopheresis (one donor will supply stimulator PBMCs, the other donor will supply responder PBMCs). If desired, the cells are frozen in fetal bovine serum and DMSO after isolation. Frozen cells may be thawed overnight in assay media (37° C., 5% CO2) and then washed and resuspended to 3×10⁶ cells/ml of assay media (RPMI; 10% fetal bovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential amino acids, 1% pyruvate). The stimulator PBMCs are prepared by irradiating the cells (about 3000 Rads).

The assay is prepared by plating in triplicate wells a mixture of:

100:1 of test sample diluted to 1% or to 0.1%,

50:1 of irradiated stimulator cells, and

50:1 of responder PBMC cells.

100 microliters of cell culture media or 100 microliter of CD4-IgG is used as the control. The wells are then incubated at 37° C., 5% CO₂ for 4 days. On day 5, each well is pulsed with tritiated thymidine (1.0 mC/well; Amersham). After 6 hours the cells are washed 3 times and then the uptake of the label is evaluated.

In another variant of this assay, PBMCs are isolated from the spleens of Balb/c mice and C57B6 mice. The cells are teased from freshly harvested spleens in assay media (RPMI; 10% fetal bovine serum, 1% penicillin/streptomycin, 1% glutamine, 1% HEPES, 1% non-essential amino acids, 1% pyruvate) and the PBMCs are isolated by overlaying these cells over Lympholyte M (Organon Teknika), centrifuging at 2000 rpm for 20 minutes, collecting and washing the mononuclear cell layer in assay media and resuspending the cells to 1×10⁷ cells/ml of assay media. The assay is then conducted as described above.

Any decreases below control is considered to be a positive result for an inhibitory compound, with decreases of less than or equal to 80% being preferred. However, any value less than control indicates an inhibitory effect for the test protein.

The following polypeptide tested positive in this assay: PRO235, PRO245 and PRO332.

Example 80 Induction of Endothelial Cell Apoptosis (ELISA) (Assay 109)

The ability of PRO polypeptides to induce apoptosis in endothelial cells was tested in human venous umbilical vein endothelial cells (HUVEC, Cell Systems) using a 96-well format, in 0% serum media supplemented with 100 ng/ml VEGF, 0.1% BSA, 1×penn/strep. A positive result in this assay indicates the usefulness of the polypeptide for therapeutically treating any of a variety of conditions associated with undesired endothelial cell growth including, for example, the inhibition of tumor growth. The 96-well plates used were manufactured by Falcon (No. 3072). Coating of 96 well plates were prepared by allowing gelatinization to occur for >30 minutes with 100 μl of 0.2% gelatin in PBS solution. The gelatin mix was aspirated thoroughly before plating HUVEC cells at a final concentration of 2×10⁴ cells/ml in 10% serum containing medium—100 μl volume per well. The cells were grown for 24 hours before adding test samples containing the PRO polypeptide of interest.

To all wells, 100 μl of 0% serum media (Cell Systems) complemented with 100 ng/ml VEGF, 0.1% BSA, 1×penn/strep was added. Test samples containing PRO polypeptides were added in triplicate at dilutions of 1%, 0.33% and 0.11%. Wells without cells were used as a blank and wells with cells only were used as a negative control. As a positive control, 1:3 serial dilutions of 50 μl of a 3×stock of staurosporine were used. The cells were incubated for 24 to 35 hours prior to ELISA.

ELISA was used to determine levels of apoptosis preparing solutions according to the Boehringer Manual [Boehringer, Cell Death Detection ELISA plus, Cat No. 1 920 685]. Sample preparations: 96 well plates were spun down at 1 krpm for 10 minutes (200 g); the supernatant was removed by fast inversion, placing the plate upside down on a paper towel to remove residual liquid. To each well, 200 μl of 1×Lysis buffer was added and incubation allowed at room temperature for 30 minutes without shaking. The plates were spun down for 10 minutes at 1 krpm, and 20 μl of the lysate (cytoplasmic fraction) was transferred into streptavidin coated MTP. 80 μl of immunoreagent mix was added to the 20 μl lystate in each well. The MTP was covered with adhesive foil and incubated at room temperature for 2 hours by placing it on an orbital shaker (200 rpm). After two hours, the supernatant was removed by suction and the wells rinsed three times with 250 μl of 1×incubation buffer per well (removed by suction). Substrate solution was added (100 μl) into each well and incubated on an orbital shaker at room temperature at 250 rpm until color development was sufficient for a photometric analysis (approx. after 10-20 minutes). A 96 well reader was used to read the plates at 405 nm, reference wavelength, 492 nm. The levels obtained for PIN 32 (control buffer) was set to 100%. Samples with levels >130% were considered positive for induction of apoptosis.

The following PRO polypeptides tested positive in this assay: PRO235.

Example 81 Human Venous Endothelial Cell Calcium Flux Assay (Assay 68)

This assay is designed to determine whether PRO polypeptides of the present invention show the ability to stimulate calcium flux in human umbilical vein endothelial cells (HUVEC, Cell Systems). Calcium influx is a well documented response upon binding of certain ligands to their receptors. A test compound that results in a positive response in the present calcium influx assay can be said to bind to a specific receptor and activate a biological signaling pathway in human endothelial cells. This could ultimately lead, for example, to endothelial cell division, inhibition of endothelial cell proliferation, endothelial tube formation, cell migration, apoptosis, etc.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) in growth media (50:50 without glycine, 1% glutamine, 10 mM Hepes, 10% FBS, 10 ng/ml bFGF), were plated on 96-well microtiter ViewPlates-96 (Packard Instrument Company Part #6005182) microtiter plates at a cell density of 2×10⁴ cells/well. The day after plating, the cells were washed three times with buffer (HBSS plus 10 mM Hepes), leaving 100 μl/well. Then 100 μl/well of 8 μM Fluo-3 (2×) was added. The cells were incubated for 1.5 hours at 37° C./5% CO₂. After incubation, the cells were then washed 3×with buffer (described above) leaving 100 μl/well. Test samples of the PRO polypeptides were prepared on different 96-well plates at 5×concentration in buffer. The positive control corresponded to 50 μM ionomycin (5×); the negative control corresponded to Protein 32. Cell plate and sample plates were run on a FLIPR (Molecular Devices) machine. The FLIPR machine added 25 μl of test sample to the cells, and readings were taken every second for one minute, then every 3 seconds for the next three minutes.

The fluorescence change from baseline to the maximum rise of the curve (Δ change) was calculated, and replicates averaged. The rate of fluorescence increase was monitored, and only those samples which had a Δ change greater than 1000 and a rise within 60 seconds, were considered positive.

The following PRO polypeptides tested positive in the present assay: PRO245.

Example 82 Fibroblast (BHK-21) Proliferation (Assay 98)

This assay shows that certain PRO polypeptides of the invention act to induce proliferation of mammalian fibroblast cells in culture and, therefore, function as useful growth factors in mammalian systems. The assay is performed as follows. BHK-21 fibroblast cells plated in standard growth medium at 2500 cells/well in a total volume of 100 μl. The PRO polypeptide, β-FGF (positive control) or nothing (negative control) are then added to the wells in the presence of 1 μg/ml of heparin for a total final volume of 200 μl. The cells are then incubated at 37° C. for 6 to 7 days. After incubation, the media is removed, the cells are washed with PBS and then an acid phosphatase substrate reaction mixture (100 μl/well) is added. The cells are then incubated at 37° C. for 2 hours. 10 μL per well of 1N NaOH is then added to stop the acid phosphatase reaction. The plates are then read at OD 405 nm. A positive in the assay is acid phosphatase activity which is at least 50% above the negative control.

The following PRO polypeptide tested positive in this assay: PRO258.

Example 83 Inhibition of Heart Adult Hypertrophy (Assay 42)

This assay is designed to measure the inhibition of heart adult hypertrophy. PRO polypeptides testing positive in this assay may find use in the therapeutic treatment of cardiac disorders associated with cardiac hypertrophy.

Ventricular myocytes are freshly isolated from adult (250 g) Harlan Sprague Dawley rats and the cells are plated at 2000/well in 180 μl volume. On day two, test samples (20 μL) containing the test PRO polypeptide are added. On day five, the cells are fixed and then stained. An increase in ANP message can also be measured by PCR from cells after a few hours. Results are based on a visual score of cell size: 0=no inhibition, −1=small inhibition, −2=large inhibition. A score of less than 0 is considered positive. Activity reference corresponds to phenylephrin (PE) at 0.1 mM, as a positive control. Assay media included: M199 (modified)-glutamine free, NaHCO₃, phenol red, supplemented with 100 nM insulin, 0.2% BSA, 5 mM cretine, 2 mM L-carnitine, 5 mM taurine, 100 U/ml penicillin G, 100 μg/ml streptomycin (CCT medium). Only inner 60 wells are used in 96 well plates. Of these, 6 wells are reserved for negative and positive (PE) controls.

The following PRO polypeptides provided a score of less than 0 in the above assay: PRO269.

Example 84 Induction of c-fos in Endothelial Cells (Assay 34)

This assay is designed to determine whether PRO polypeptides show the ability to induce c-fos in endothelial cells. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of conditions or disorders where angiogenesis would be beneficial including, for example, wound healing, and the like (as would agonists of these PRO polypeptides). Antagonists of the PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of cancerous tumors.

Human venous umbilical vein endothelial cells (HUVEC, Cell Systems) in growth media (50% Ham's F12 w/o GHT: low glucose, and 50% DMEM without glycine: with NaHCO3, 1% glutamine, 10 mM HEPES, 10% FBS, 10 ng/ml bFGF) were plated on 96-well microtiter plates at a cell density of 1×10⁴ cells/well. The day after plating, the cells were starved by removing the growth media and treating the cells with 100 μl/well test samples and controls (positive control=growth media; negative control =Protein 32 buffer=10 mM HEPES, 140 mM NaCl, 4% (w/v) mannitol, pH 6.8). The cells were incubated for 30 minutes at 37° C, in 5% CO₂. The samples were removed, and the first part of the bDNA kit protocol (Chiron Diagnostics, cat. #6005-037) was followed, where each capitalized reagent/buffer listed below was available from the kit.

Briefly, the amounts of the TM Lysis Buffer and Probes needed for the tests were calculated based on information provided by the manufacturer. The appropriate amounts of thawed Probes were added to the TM Lysis Buffer. The Capture Hybridization Buffer was warmed to room temperature. The bDNA strips were set up in the metal strip holders, and 100 μl of Capture Hybridization Buffer was added to each b-DNA well needed, followed by incubation for at least 30 minutes. The test plates with the cells were removed from the incubator, and the media was gently removed using the vacuum manifold. 100 μl of Lysis Hybridization Buffer with Probes were quickly pipetted into each well of the microtiter plates. The plates were then incubated at 55° C. for 15 minutes. Upon removal from the incubator, the plates were placed on the vortex mixer with the microtiter adapter head and vortexed on the #2 setting for one minute. 80 μl of the lysate was removed and added to the bDNA wells containing the Capture Hybridization Buffer, and pipetted up and down to mix. The plates were incubated at 53° C. for at least 16 hours.

On the next day, the second part of the bDNA kit protocol was followed. Specifically, the plates were removed from the incubator and placed on the bench to cool for 10 minutes. The volumes of additions needed were calculated based upon information provided by the manufacturer. An Amplifier Working Solution was prepared by making a 1:100 dilution of the Amplifier Concentrate (20 fm/μl) in AL Hybridization Buffer. The hybridization mixture was removed from the plates and washed twice with Wash A. 50μl of Amplifier Working Solution was added to each well and the wells were incubated at 53° C. for 30 minutes. The plates were then removed from the incubator and allowed to cool for 10 minutes. The Label Probe Working Solution was prepared by making a 1:100 dilution of Label Concentrate (40 pmoles/μl) in AL Hybridization Buffer. After the 10-minute cool-down period, the amplifier hybridization mixture was removed and the plates were washed twice with Wash A. 50 μl of Label Probe Working Solution was added to each well and the wells were incubated at 53° C. for 15 minutes. After cooling for 10 minutes, the Substrate was warmed to room temperature. Upon addition of 3 μl of Substrate Enhancer to each ml of Substrate needed for the assay, the plates were allowed to cool for 10 minutes, the label hybridization mixture was removed, and the plates were washed twice with Wash A and three times with Wash D. 50 μl of the Substrate Solution with Enhancer was added to each well. The plates were incubated for 30 minutes at 37° C. and RLU was read in an appropriate luminometer.

The replicates were averaged and the coefficient of variation was determined. The measure of activity of the fold increase over the negative control (Protein 32/HEPES buffer described above) value was indicated by chemiluminescence units (RLU). The results are considered positive if the PRO polypeptide exhibits at least a two-fold value over the negative buffer control. Negative control=1.00 RLU at 1.00% dilution. Positive control=8.39 RLU at 1.00% dilution.

The following PRO polypeptides tested positive in this assay: PRO287.

Example 85 Guinea Pig Vascular Leak (Assays 32 and 51)

This assay is designed to determine whether PRO polypeptides of the present invention show the ability to induce vascular permeability. Polypeptides testing positive in this assay are expected to be useful for the therapeutic treatment of conditions which would benefit from enhanced vascular permeability including, for example, conditions which may benefit from enhanced local immune system cell infiltration.

Hairless guinea pigs weighing 350 grams or more were anesthetized with Ketamine (75-80 mg/kg) and 5 mg/kg Xylazine intramuscularly. Test samples containing the PRO polypeptide or a physiological buffer without the test polypeptide are injected into skin on the back of the test animals with 100 μl per injection site intradermally. There were approximately 16-24 injection sites per animal. One ml of Evans blue dye (1% in PBS) is then injected intracardially. Skin vascular permeability responses to the compounds (i.e., blemishes at the injection sites of injection) are visually scored by measuring the diameter (in mm) of blue-colored leaks from the site of injection at 1 and 6 hours post administration of the test materials. The mm diameter of blueness at the site of injection is observed and recorded as well as the severity of the vascular leakage. Blemishes of at least 5 mm in diameter are considered positive for the assay when testing purified proteins, being indicative of the ability to induce vascular leakage or permeability. A response greater than 7 mm diameter is considered positive for conditioned media samples. Human VEGF at 0.1 μg/100 μl is used as a positive control, inducing a response of 15-23 mm diameter.

The following PRO polypeptides tested positive in this assay: PRO302 and PRO533.

Example 86 Detection of Endothelial Cell Apoptosis (FACS) (Assay 96)

The ability of PRO polypeptides of the present invention to induce apoptosis in endothelial cells was tested in human venous umbilical vein endothelial cells (HUVEC, Cell Systems) in gelatinized T175 flasks using HUVEC cells below passage 10. PRO polypeptides testing positive in this assay are expected to be useful for therapeutically treating conditions where apoptosis of endothelial cells would be beneficial including, for example, the therapeutic treatment of tumors.

On day one, the cells were split [420,000 cells per gelatinized 6 cm dishes—(11×10³ cells/cm² Falcon, Primaria)] and grown in media containing serum (CS-C, Cell System) overnight or for 16 hours to 24 hours.

On day 2, the cells were washed 1× with 5 ml PBS; 3 ml of 0% serum medium was added with VEGF (100 ng/ml); and 30 μl of the PRO test compound (final dilution 1%) or 0% serum medium (negative control) was added. The mixtures were incubated for 48 hours before harvesting.

The cells were then harvested for FACS analysis. The medium was aspirated and the cells washed once with PBS. 5 ml of 1×trypsin was added to the cells in a T-175 flask, and the cells were allowed to stand until they were released from the plate (about 5-10 minutes). Trypsinization was stopped by adding 5 ml of growth media. The cells were spun at 1000 rpm for 5 minutes at 4° C. The media was aspirated and the cells were resuspended in 10 ml of 10% serum complemented medium (Cell Systems), 5 μl of Annexin-FITC (BioVison) added and chilled tubes were submitted for FACS. A positive result was determined to be enhanced apoptosis in the PRO polypeptide treated samples as compared to the negative control.

The following PRO polypeptides tested positive in this assay: PRO331.

Example 87 Induction of c-fos in Cortical Neurons (Assay 83)

This assay is designed to determine whether PRO polypeptides show the ability to induce c-fos in cortical neurons. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of nervous system disorders and injuries where neuronal proliferation would be beneficial.

Cortical neurons are dissociated and plated in growth medium at 10,000 cells per well in 96 well plates. After approximately 2 cellular divisions, the cells are treated for 30 minutes with the PRO polypeptide or nothing (negative control). The cells are then fixed for 5 minutes with cold methanol and stained with an antibody directed against phosphorylated CREB. mRNA levels are then calculated using chemiluminescence. A positive in the assay is any factor that results in at least a 2-fold increase in c-fos message as compared to the negative controls.

The following PRO polypeptides tested positive in this assay: PRO229 and PRO269.

Example 88 Stimulation of Endothelial Tube Formation (Assay 85)

This assay is designed to determine whether PRO polypeptides show the ability to promote endothelial vacuole and lumen formation in the absence of exogenous growth factors. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where endothelial vacuole and/or lumen formation would be beneficial including, for example, where the stimulation of pinocytosis, ion pumping, vascular permeability and/or junctional formation would be beneficial.

HUVEC cells (passage <8 from primary) are mixed with type I rat tail collagen (final concentration 2.6 mg/ml) at a density of 6×10⁵ cells per ml and plated at 50 μl per well of M199 culture media supplement with 1% FBS and 1 μM 6-FAM-FITC dye to stain the vacuoles while they are forming and in the presence of the PRO polypeptide. The cells are then incubated at 37° C./5% CO₂ for 48 hours, fixed with 3.7% formalin room temperature for 10 minutes, washed 5 times with M199 medium and then stained with Rh-Phalloidin at 4° C. overnight followed by nuclear staining with 4 μM DAPI. A positive result in the assay is when vacuoles are present in greater than 50% of the cells.

The following PRO polypeptides tested positive in this assay: PRO230.

Example 89 Detection of Polypeptides That Affect Glucose and/or FFA Uptake in Skeletal Muscle (Assay 106)

This assay is designed to determine whether PRO polypeptides show the ability to affect glucose or FFA uptake by skeletal muscle cells. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where either the stimulation or inhibition of glucose uptake by skeletal muscle would be beneficial including, for example, diabetes or hyper- or hypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primary rat differentiated skeletal muscle, and allowed to incubate overnight. Then fresh media with the PRO polypeptide and +/− insulin are added to the wells. The sample media is then monitored to determine glucose and FFA uptake by the skeletal muscle cells. The insulin will stimulate glucose and FFA uptake by the skeletal muscle, and insulin in media without the PRO polypeptide is used as a positive control, and a limit for scoring. As the PRO polypeptide being tested may either stimulate or inhibit glucose and FFA uptake, results are scored as positive in the assay if greater than 1.5 times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as either stimulators or inhibitors of glucose and/or FFA uptake in this assay: PRO187, PRO211, PRO221, PRO222, PRO224, PRO230, PRO239, PRO231, PRO245, PRO247, PRO258, PRO269, PRO328 and PRO533.

Example 90 Rod Photoreceptor Cell Survival Assay (Assay 46)

This assay shows that certain polypeptides of the invention act to enhance the survival/proliferation of rod photoreceptor cells and, therefore, are useful for the therapeutic treatment of retinal disorders or injuries including, for example, treating sight loss in mammals due to retinitis pigmentosum, AMD, etc.

Sprague Dawley rat pups (postnatal day 7, mixed population: glia and netinal neural cell types) are killed by decapitation following CO₂ anesthesia and the eyes removed under sterile conditions. The neural retina is dissected away from the pigment epithelium and other ocular tissue and then dissociated into a single cell suspension using 0.25% trypsin in Ca²⁺, Mg²⁺-free PBS. The retinas are incubated at 37° C. in this solution for 7-10 minutes after which the trypsin is inactivated by adding 1 ml soybean trypsin inhibitor. The cells are plated at a density of approximately 10,000 cells/ml into 96 well plates in DMEM/F12 supplemented with N₂. Cells for all experiments are grown at 37° C. in a water saturated atmosphere of 5% CO₂. After 7-10 days in culture, the cells are stained using calcein AM or CellTracker Green CMFDA and then fixed using 4% paraformaldehyde. Rho 4D2 (ascities or IgG 1:100) monoclonal antibody directed towards the visual pigment rhodopsin is used to detect rod photoreceptor cells by indirect immunofluorescence. The results are calculated as % survival: total number of calcein—rhodopsin positive cells at 7-10 days in culture, divided by the total number of rhodopsin positive cells at time 7-10 days in culture. The total cells (fluorescent) are quantified at 20×objective magnification using a CCD camera and NIH image software for MacIntosh. Fields in the well are chosen at random.

The following polypeptides tested positive in this assay: PRO245.

Example 91 In Vitro Antitumor Assay (Assay 161)

The antiproliferative activity of various PRO polypeptides was determined in the investigational, disease-oriented in vitro anti-cancer drug discovery assay of the National Cancer Institute (NCI), using a sulforhodamine B (SRB) dye binding assay essentially as described by Skehan et al., J. Natl. Cancer Inst. 82:1107-1112 (1990). The 60 tumor cell lines employed in this study (“the NCI panel”), as well as conditions for their maintenance and culture in vitro have been described by Monks et al., J. Natl. Cancer Inst. 83:757-766 (1991). The purpose of this screen is to initially evaluate the cytotoxic and/or cytostatic activity of the test compounds against different types of tumors (Monks et al., supra; Boyd, Cancer: Princ. Pract. Oncol. Update 3(10):1-12 [1989]).

Cells from approximately 60 human tumor cell lines were harvested with trypsin/EDTA (Gibco), washed once, resuspended in IMEM and their viability was determined. The cell suspensions were added by pipet (100 μL volume) into separate 96-well microtiter plates. The cell density for the 6-day incubation was less than for the 2-day incubation to prevent overgrowth. Inoculates were allowed a preincubation period of 24 hours at 37° C. for stabilization. Dilutions at twice the intended test concentration were added at time zero in 100 μL aliquots to the microtiter plate wells (1:2 dilution). Test compounds were evaluated at five half-log dilutions (1000 to 100,000-fold). Incubations took place for two days and six days in a 5% CO₂ atmosphere and 100% humidity.

After incubation, the medium was removed and the cells were fixed in 0.1 ml of 10% trichloroacetic acid at 40° C. The plates were rinsed five times with deionized water, dried, stained for 30 minutes with 0.1 ml of 0.4% sulforhodamine B dye (Sigma) dissolved in 1% acetic acid, rinsed four times with 1% acetic acid to remove unbound dye, dried, and the stain was extracted for five minutes with 0.1 ml of 10 mM Tris base [tris(hydroxymethyl)aminomethane], pH 10.5. The absorbance (OD) of sulforhodamine B at 492 nm was measured using a computer-interfaced, 96-well microtiter plate reader.

A test sample is considered positive if it shows at least 50% growth inhibitory effect at one or more concentrations. PRO polypeptides testing positive in this assay are shown in Table 7, where the abbreviations are as follows:

NSCL=non-small cell lung carcinoma

CNS=central nervous system

TABLE 7 Test compound Tumor Cell Line Type Cell Line Designation PRO211 NSCL HOP62 PRO211 Leukemia RPMI-8226 PRO211 Leukemia HL-60 (TB) PRO211 NSCL NCI-H522 PRO211 CNS SF-539 PRO211 Melanoma LOX IMVI PRO211 Breast MDA-MB-435 PRO211 Leukemia MOLT-4 PRO211 CNS U251 PRO211 Breast MCF7 PRO211 Leukemia HT-60 (TB) PRO211 Leukemia MOLT-4 PRO211 NSCL EKVX PRO211 NSCL NCI-H23 PRO211 NSCL NCI-H322M PRO211 NSCL NCI-H460 PRO211 Colon HCT-116 PRO211 Colon HT29 PRO211 CNS SF-268 PRO211 CNS SF-295 PRO211 CNS SNB-19 PRO211 CNS U251 PRO211 Melanoma LOX IMVI PRO211 Melanoma SK-MEL-5 PRO211 Melanoma UACC-257 PRO211 Melanoma UACC-62 PRO211 Ovarian OVCAR-8 PRO211 Renal RXF 393 PRO211 Breast MCF7 PRO211 Breast NCI/ADR-REHS 578T PRO211 Breast T-47D PRO211 Leukemia HL-60 (TB) PRO211 Leukemia SR PRO211 NSCL NCI-H23 PRO211 Colon HCT-116 PRO211 Melanoma LOX-IMVI PRO211 Melanoma SK-MEL-5 PRO211 Breast T-47D PRO228 Leukemia MOLT-4 PRO228 NSCL EKVX PRO228 Colon KM12 PRO228 Melanoma UACC-62 PRO228 Ovarian OVCAR-3 PRO228 Renal TK10 PRO228 Renal SN12C PRO228 Breast MCF7 PRO228 Leukemia CCRF-CEM PRO228 Leukemia HL-60 (TB) PRO228 Colon COLO 205 PRO228 Colon HCT-15 PRO228 Colon KM12 PRO228 CNS SF-268 PRO228 CNS SNB-75 PRO228 Melanoma LOX-IMVI PRO228 Melanoma SK-MEL2 PRO228 Melanoma UACC-257 PRO228 Ovarian IGROV1 PRO228 Ovarian OVCAR-4 PRO228 Ovarian OVCAR-5 PRO228 Ovarian OVCAR-8 PRO228 Renal 786-0 PRO228 Renal CAKI-1 PRO228 Renal RXF 393 PRO228 Renal TK-10 PRO228 Renal UO-31 PRO228 Prostate PC-3 PRO228 Prostate DU-145 PRO228 Breast MCF7 PRO228 Breast NCI/ADR-REHS 578T PRO228 Breast MDA-MB-435MDA-N PRO228 Breast T-47D PRO219 Leukemia SR PRO219 NSCL NCI-H5222 PRO219 Breast MCF7 PRO219 Leukemia K-562; RPMI-8226 PRO219 NSCL HOP-62; NCI-H322M PRO219 NSCL NCI-H460 PRO219 Colon HT29; KM12; HCT-116 PRO219 CNS SF-539; U251 PRO219 Prostate DU-145 PRO219 Breast MDA-N PRO219 Ovarian IGROV1 PRO219 NSCL NCI-H226 PRO219 Leukemia MOLT-4 PRO219 NSCL A549/ATCC; EKVX; NCI-H23 PRO219 Colon HCC-2998 PRO219 CNS SF-295; SNB-19 PRO219 Melanoma SK-MEL-2; SK-MEL-5 PRO219 Melanoma UACC-257; UACC-62 PRO219 Ovarian OCAR-4; SK-OV-3 PRO219 Renal 786-0; ACHN; CAKI-1; SN12C PRO219 Renal TK-10; UO-31 PRO219 Breast NCI/ADR-RES; BT-549; T-47D PRO219 Breast MDA-MB-435 PRO221 Leukemia CCRF-CEM PRO221 Leukemia MOLT-4 PRO221 NSCL HOP-62 PRO221 Breast MDA-N PRO221 Leukemia RPMI-8226; SR PRO221 NSCL NCI-H460 PRO221 Colon HCC-2998 PRO221 Ovarian IGROV1 PRO221 Renal TK-10 PRO221 Breast MCF7 PRO221 Leukemia K-562 PRO221 Breast MDA-MB-435 PRO224 Ovarian OVCAR-4 PRO224 Renal RXF 393 PRO224 Prostate DU-145 PRO224 NSCL HOP-62; NCI-H322M PRO224 Melanoma LOX IMVI PRO224 Ovarian OVCAR-8 PRO224 Leukemia SR PRO224 NSCL NCI-H460 PRO224 CNS SF-295 PRO224 Leukemia RPMI-8226 PRO224 Breast BT-549 PRO224 Leukemia CCRF-CEM; LH-60 (TB) PRO224 Colon HCT-116 PRO224 Breast MDA-MB-435 PRO224 Leukemia HL-60 (TB) PRO224 Colon HCC-2998 PRO224 Prostate PC-3 PRO224 CNS U251 PRO224 Colon HCT-15 PRO224 CNS SF-539 PRO224 Renal ACHN PRO328 Leukemia RPMI-8226 PRO328 NSCL A549/ATCC; EKVX; HOP-62 PRO328 NSCL NCI-H23; NCI-H322M PRO328 Colon HCT-15; KM12 PRO328 CNS SF-295; SF-539; SNB-19; U251 PRO328 Melanoma M14; UACC-257; UCAA-62 PRO328 Renal 786-0; ACHN PRO328 Breast MCF7 PRO328 Leukemia SR PRO328 Colon NCI-H23 PRO328 Melanoma SK-MEL-5 PRO328 Prostate DU-145 PRO328 Melanoma LOX IMVI PRO328 Breast MDA-MB-435 PRO328 Ovarian OVCAR-3 PRO328 Breast T-47D PRO301 NSCL NCI-H322M PRO301 Leukemia MOLT-4; SR PRO301 NSCL A549/ATCC; EKVX; PRO301 NSCL NCI-H23; NCI-460; NCI-H226 PRO301 Colon COLO 205; HCC-2998; PRO301 Colon HCT-15; KM12; HT29; PRO301 Colon HCT-116 PRO301 CNS SF-268; SF-295; SNB-19 PRO301 Melanoma MALME-3M; SK-MEL-2; PRO301 Melanoma SK-MEL-5;UACC-257 PRO301 Melanoma UACC-62 PRO301 Ovarian IGROV1; OVCAR-4 PRO301 Ovarian OVCAR-5 PRO301 Ovarian OVCAR-8; SK0OV-3 PRO301 Renal ACHN; CAKI-1; TK-10; UO-31 PRO301 Prostate PC-3; DU-145 PRO301 Breast NCI/ADR-RES; HS 578T PRO301 Breast MDA-MB-435; MDA-N; T-47D PRO301 Melanoma M14 PRO301 Leukemia CCRF-CEM; HL-60(TB); K-562 PRO301 Leukemia RPMI-8226 PRO301 Melanoma LOX IMVI PRO301 Renal 786-0; SN12C PRO301 Breast MCF7; MDA-MB-231/ATCC PRO301 Breast BT-549 PRO301 NSCL HOP-62 PRO301 CNS SF-539 PRO301 Ovarian OVCAR-3 PRO326 NSCL NCI-H322M PRO326 CNS SF295 PRO326 CNS ST539 PRO326 CNS U251

The results of these assays demonstrate that the positive testing PRO polypeptides are useful for inhibiting neoplastic growth in a number of different tumor cell types and may be used therapeutically therefor. Antibodies against these PRO polypeptides are useful for affinity purification of these useful polypeptides. Nucleic acids encoding these PRO polypeptides are useful for the recombinant preparation of these polypeptides.

Example 92 Gene Amplification

This example shows that certain PRO polypeptide-encoding genes are amplified in the genome of certain human lung, colon and/or breast cancers and/or cell lines. Amplification is associated with overexpression of the gene product, indicating that the polypeptides are useful targets for therapeutic intervention in certain cancers such as colon, lung, breast and other cancers and diagnostic determination of the presence of those cancers. Therapeutic agents may take the form of antagonists of the PRO polypeptide, for example, murine-human chimeric, humanized or human antibodies against a PRO polypeptide.

The starting material for the screen was genomic DNA isolated from a variety cancers. The DNA is quantitated precisely, e.g., fluorometrically. As a negative control, DNA was isolated from the cells of ten normal healthy individuals which was pooled and used as assay controls for the gene copy in healthy individuals (not shown). The 5′ nuclease assay (for example, TaqMan™) and real-time quantitative PCR (for example, ABI Prizm 7700 Sequence Detection System™ (Perkin Elmer, Applied Biosystems Division, Foster City, Calif.)), were used to find genes potentially amplified in certain cancers. The results were used to determine whether the DNA encoding the PRO polypeptide is over-represented in any of the primary lung or colon cancers or cancer cell lines or breast cancer cell lines that were screened. The primary lung cancers were obtained from individuals with tumors of the type and stage as indicated in Table 8. An explanation of the abbreviations used for the designation of the primary tumors listed in Table 8 and the primary tumors and cell lines referred to throughout this example are given below.

The results of the TaqMan™ are reported in delta (Δ) Ct units. One unit corresponds to 1 PCR cycle or approximately a 2-fold amplification relative to normal, two units corresponds to 4-fold, 3 units to 8-fold amplification and so on. Quantitation was obtained using primers and a TaqMan™ fluorescent probe derived from the PRO polypeptide-encoding gene. Regions of the PRO polypeptide-encoding gene which are most likely to contain unique nucleic acid sequences and which are least likely to have spliced out introns are preferred for the primer and probe derivation, e.g., 3′-untranslated regions. The sequences for the primers and probes (forward, reverse and probe) used for the PRO polypeptide gene amplification analysis were as follows:

PRO187 (DNA27864-1155) 27864.tm.p: 5′-GCAGATTTTGAGGACAGCCACCTCCA-3′ (SEQ ID NO:381) 27864.tm.f: 5′-GGCCTTGCAGACAACCGT-3′ (SEQ ID NO:382) 27864.tm.r: 5′-CAGACTGAGGGAGATCCGAGA-3′ (SEQ ID NO:383) 27864.tm.p2: 5′-CAGCTGCCCTTCCCCAACCA-3′ (SEQ ID NO:384) 27864.tm.f2: 5′-CATCAAGCGCCTCTACCA-3′ (SEQ ID NO:385) 27864.tm.r2: 5′-CACAAACTCGAACTGCTTCTG-3′ (SEQ ID NO:386) PRO214 (DNA32286-1191): 32286.3utr-5: 5′-GGGCCATCACAGCTCCCT-3′ (SEQ ID NO:387) 32286.3utr-3b: 5′-GGGATGTGGTGAACACAGAACA-3′ (SEQ ID NO:388) 32286.3utr-probe: 5′-TGCCAGCTGCATGCTGCCAGTT-3′ (SEQ ID NO:389) PRO211 (DNA32292-1131): 32292.3utr-5: 5′-CAGAAGGATGTCCCGTGGAA-3′ (SEQ ID NO:390) 32292.3utr-3: 5′-GCCGCTGTCCACTGCAG-3′ (SEQ ID NO:391) 32292.3utr-probe.rc: 5′-GACGGCATCCTCAGGGCCACA-3′ (SEQ ID NO:392) PRO230 (DNA33223-1136): 33223.tm.p3: 5′-ATGTCCTCCATGCCCACGCG-3′ (SEQ ID NO:393) 33223.tm.f3: 5′-GAGTGCGACATCGAGAGCTT-3′ (SEQ ID NO:394) 33223.tm.r3: 5′-CCGCAGCCTCAGTGATGA-3′ (SEQ ID NO:395) 33223.3utr-5: 5′-GAAGAGCACAGCTGCAGATCC-3′ (SEQ ID NO:396) 33223.3utr-3: 5′-GAGGTGTCCTGGCTTTGGTAGT-3′ (SEQ ID NO:397) 33223.3utr-probe: 5′-CCTCTGGCGCCCCCACTCAA-3′ (SEQ ID NO:398) PRO317 (DNA33461-1199): 33461.tm.f: 5′-CCAGGAGAGCTGGCGATG-3′ (SEQ ID NO:399) 33461.tm.r: 5′-GCAAATTCAGGGCTCACTAGAGA-3′ (SEQ ID NO:400) 33461.tm.p: 5′-CACAGAGCATTTGTCCATCAGCAGT (SEQ ID NO:401) TCAG-3′ PRO246 (DNA35639-1172): 35639.3utr-5: 5′-GGCAGAGACTTCCAGTCACTGA-3′ (SEQ ID NO:402) 35639.3utr-3: 5′-GCCAAGGGTGGTGTTAGATAGG-3′ (SEQ ID NO:403) 35639.3utr-probe: 5′-CAGGCCCCCTTGATCTGTACCCCA-3′ (SEQ ID NO:404) PRO533 (DNA49435-1219): 49435.tm.f: 5′-GGGACGTGCTTCTACAAGAACAG-3′ (SEQ ID NO:405) 49435.tm.r: 5′-CAGGCTTACAATGTTATGATCAGACA-3′ (SEQ ID NO:406) 49435.tm.p: 5′-TATTCAGAGTTTTCCATTGGCAGTGCC (SEQ ID NO:407) AGTT-3′ PRO343 (DNA43318-1217): 43318.tm.f1 5′-TCTACATCAGCCTCTCTGCGC-3′ (SEQ ID NO:408) 43318.tm.p1 5′-CGATCTTCTCCACCCAGGAGCGG-3′ (SEQ ID NO:409) 43318.tm.r1 5′-GGAGCTGCACCCCTTGC-3′ (SEQ ID NO:237) PRO232 (DNA34435-1140): 34435.3utr-5: 5′-GCCAGGCCTCACATTCGT-3′ (SEQ ID NO:410) DNA34435.3utr-probe: 5′-CTCCCTGAATGGCAGCCTGAGCA-3′ (SEQ ID NO:411) DNA34435.3utr-3: 5′-AGGTGTTTATTAAGGGCCTACGCT-3′ (SEQ ID NO:412) PRO269 (DNA38260-1180): 38260.tm.f: 5′-CAGAGCAGAGGGTGCCTTG-3′ (SEQ ID NO:413 3826O.tm.p: 5′-TGGCGGAGTCCCCTCTTGGCT-3′ (SEQ ID NO:414) 38260.tm.r: 5′-CCCTGTTTCCCTATGCATCACT-3′ (SEQ ID NO:415) PRO304 (DNA39520-1217): 39520.tm.f: 5′-TCAACCCCTGACCCTTTCCTA-3′ (SEQ ID NO:416) 3952O.tm.p: 5′-GGCAGGGGACAAGCCATCTCTCCT-3′ (SEQ ID NO:417) 39520.tm.r: 5′-GGGACTGAACTGCCAGCTTC-3′ (SEQ ID NO:418) PRO339 (DNA43466-1225): 43466.tm.f1: 5′-GGGCCCTAACCTCATTACCTTT-3′ (SEQ ID NO:419) 43466.tm.p1: 5′-TGTCTGCCTCAGCCCCAGGAAGG-3′ (SEQ ID NO:420) 43466.tm.r1: 5′-TCTGTCCACCATCTTGCCTTG-3′ (SEQ ID NO:421)

The 5′ nuclease assay reaction is a fluorescent PCR-based technique which makes use of the 5′ exonuclease activity of Taq DNA polymerase enzyme to monitor amplification in real time. Two oligonucleotide primers (forward [.f] and reverse [.r]) are used to generate an amplicon typical of a PCR reaction. A third oligonucleotide, or probe (.p), is designed to detect nucleotide sequence located between the two PCR primers. The probe is non-extendible by Taq DNA polymerase enzyme, and is labeled with a reporter fluorescent dye and a quencher fluorescent dye. Any laser-induced emission from the reporter dye is quenched by the quenching dye when the two dyes are located close together as they are on the probe. During the amplification reaction, the Taq DNA polymerase enzyme cleaves the probe in a template-dependent manner. The resultant probe fragments disassociate in solution, and signal from the released reporter dye is free from the quenching effect of the second fluorophore. One molecule of reporter dye is liberated for each new molecule synthesized, and detection of the unquenched reporter dye provides the basis for quantitative interpretation of the data.

The 5′ nuclease procedure is run on a real-time quantitative PCR device such as the ABI Prism 7700TM Sequence Detection. The system consists of a thermocycler, laser, charge-coupled device (CCD) camera and computer. The system amplifies samples in a 96-well format on a thermocycler. During amplification, laser-induced fluorescent signal is collected in real-time through fiber optics cables for all 96 wells, and detected at the CCD. The system includes software for running the instrument and for analyzing the data.

5′ Nuclease assay data are initially expressed as Ct, or the threshold cycle. This is defined as the cycle at which the reporter signal accumulates above the background level of fluorescence. The ΔCt values are used as quantitative measurement of the relative number of starting copies of a particular target sequence in a nucleic acid sample when comparing cancer DNA results to normal human DNA results.

Table 8 describes the stage, T stage and N stage of various primary tumors which were used to screen the PRO polypeptide compounds of the invention.

TABLE 8 Primary Lung and Colon Tumor Profiles Primary Tumor Stage Stage Other Stage Dukes Stage T Stage N Stage Human lung tumor AdenoCa (SRCC724) [LT1] IIA T1 N1 Human lung tumor SqCCa (SRCC725) [LT1a] IIB T3 N0 Human lung tumor AdenoCa (SRCC726) [LT2] IB T2 N0 Human lung tumor AdenoCa (SRCC727) [LT3] IIIA T1 N2 Human lung tumor AdenoCa (SRCC728) [LT4] IB T2 N0 Human lung tumor SqCCa (SRCC729) [LT6] IB T2 N0 Human lung tumor Aden/SqCCa (SRCC730) [LT7] IA T1 N0 Human lung tumor AdenoCa (SRCC731) [LT9] IB T2 N0 Human lung tumor SqCCa (SRCC732) [LT10] IIB T2 N1 Human lung tumor SqCCa (SRCC733) [LT11] IIA T1 N1 Human lung tumor AdenoCa (SRCC734) [LT12] IV T2 N0 Human lung tumor AdenoSqCCa (SRCC735)[LT13] IB T2 N0 Human lung tumor SqCCa (SRCC736) [LT15] IB T2 N0 Human lung tumor SqCCa (SRCC737) [LT16] IB T2 N0 Human lung tumor SqCCa (SRCC738) [LT17] IIB T2 N1 Human lung tumor SqCCa (SRCC739) [LT18] IB T2 N0 Human lung tumor SqCCa (SRCC740) [LT19] IB T2 N0 Human lung tumor LCCa (SRCC741) [LT21] IIB T3 N1 Human lung AdenoCa (SRCC811) [LT22] 1A T1 N0 Human colon AdenoCa (SRCC742) [CT2] M1 D pT4 N0 Human colon AdenoCa (SRCC743) [CT3] B pT3 N0 Human colon AdenoCa (SRCC744) [CT8] B T3 N0 Human colon AdenoCa (SRCC745) [CT10] A pT2 N0 Human colon AdenoCa (SRCC746) [CT12] MO, R1 B T3 N0 Human colon AdenoCa (SRCC747) [CT14] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC748) [CT15] M1, R2 D T4 N2 Human colon AdenoCa (SRCC749) [CT16] pMO B pT3 pN0 Human colon AdenoCa (SRCC750) [CT17] C1 pT3 pN1 Human colon AdenoCa (SRCC751) [CT1] MO, R1 B pT3 N0 Human colon AdenoCa (SRCC752) [CT4] B pT3 M0 Human colon AdenoCa (SRCC753) [CT5] G2 C1 pT3 pN0 Human colon AdenoCa (SRCC754) [CT6] pMO, RO B pT3 pN0 Human colon AdenoCa (SRCC755) [CT7] G1 A pT2 pN0 Human colon AdenoCa (SRCC756) [CT9] G3 D pT4 pN2 Human colon AdenoCa (SRCC757) [CT11] B T3 N0 Human colon AdenoCa (SRCC758) [CT18] MO, RO B pT3 pN0

DNA Preparation

DNA was prepared from cultured cell lines, primary tumors, normal human blood. The isolation was performed using purification kit, buffer set and protease and all from Quiagen, according to the manufacturer's instructions and the description below.

Cell Culture Lysis

Cells were washed and trypsinized at a concentration of 7.5×108 per tip and pelleted by centrifuging at 1000 rpm for 5 minutes at 4° C., followed by washing again with 1/2 volume of PBS recentrifugation. The pellets were washed a third time, the suspended cells collected and washed 2× with PBS. The cells were then suspended into 10 ml PBS. Buffer C1 was equilibrated at 4° C. Qiagen protease #19155 was diluted into 6.25 ml cold ddH₂O to a final concentration of 20 mg/ml and equilibrated at 4° C. 10 ml of G2 Buffer w by diluting Qiagen RNAse A stock (100 mg/ml) to a final concentration of 200 μg/ml.

Buffer C1 (10 ml, 4° C.) and ddH2O (40 ml, 4° C.) were then added to the 10 ml of cell suspension, mixed by inverting and incubated on ice for 10 minutes. The cell nuclei were pelleted by centrifuging in a Beckman swinging bucket rotor at 2500 rpm at 4° C. for 15 minutes. The supernatant was discarded and the nuclei were suspended with a vortex into 2 ml Buffer C1 (at 4° C.) and 6 ml ddH₂O, followed by a second 4° C. centrifugation at 2500 rpm for 15 minutes. The nuclei were then resuspended into the residual buffer using 200 μl per tip. G2 buffer (10 ml) was added to the suspended nuclei while gentle vortexing was applied. Upon completion of buffer addition, vigorous vortexing was applied for 30 seconds. Quiagen protease (200 μl, prepared as indicated above) was added and incubated at 50° C. for 60 minutes. The incubation and centrifugation was repeated until the lysates were clear (e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4° C.)

Solid Human Tumor Sample Preparation and Lysis

Tumor samples were weighed and placed into 50 ml conical tubes and held on ice. Processing was limited to no more than 250 mg tissue per preparation (1 tip/preparation). The protease solution was freshly prepared by diluting into 6.25 ml cold ddH₂O to a final concentration of 20 mg/ml and stored at 4° C. G2 buffer (20 ml) was prepared by diluting DNAse A to a final concentration of 200 mg/ml (from 100 mg/ml stock). The tumor tissue was homogenated in 19 ml G2 buffer for 60 seconds using the large tip of the polytron in a laminar-flow TC hood in order to avoid inhalation of aerosols, and held at room temperature. Between samples, the polytron was cleaned by spinning at 2×30 seconds each in 2L ddH₂O, followed by G2 buffer (50 ml). If tissue was still present on the generator tip, the apparatus was disassembled and cleaned.

Quiagen protease (prepared as indicated above, 1.0 ml) was added, followed by vortexing and incubation at 50° C. for 3 hours. The incubation and centrifugation was repeated until the lysates were clear (e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4° C.).

Human Blood Preparation and Lysis

Blood was drawn from healthy volunteers using standard infectious agent protocols and citrated into 10 ml samples per tip. Quiagen protease was freshly prepared by dilution into 6.25 ml cold ddH₂O to a final concentration of 20 mg/ml and stored at 4° C. G2 buffer was prepared by diluting RNAse A to a final concentration of 200 μg/ml from 100 mg/ml stock. The blood (10 ml) was placed into a 50 ml conical tube and 10 ml C1 buffer and 30 ml ddH₂O (both previously equilibrated to 4° C.) were added, and the components mixed by inverting and held on ice for 10 minutes. The nuclei were pelleted with a Beckman swinging bucket rotor at 2500 rpm, 4° C. for 15 minutes and the supernatant discarded. With a vortex, the nuclei were suspended into 2 ml C1 buffer (4° C.) and 6 ml ddH₂O (4° C.). Vortexing was repeated until the pellet was white. The nuclei were then suspended into the residual buffer using a 200 μl tip. G2 buffer (10 ml) were added to the suspended nuclei while gently vortexing, followed by vigorous vortexing for 30 seconds. Quiagen protease was added (200 μl) and incubated at 50° C. for 60 minutes. The incubation and centrifugation was repeated until the lysates were clear (e.g., incubating additional 30-60 minutes, pelleting at 3000×g for 10 min., 4° C.).

Purification of Cleared Lysates

(1) Isolation of Genomic DNA:

Genomic DNA was equilibrated (I sample per maxi tip preparation) with 10 ml QBT buffer. QF elution buffer was equilibrated at 50° C. The samples were vortexed for 30 seconds, then loaded onto equilibrated tips and drained by gravity. The tips were washed with 2×15 ml QC buffer. The DNA was eluted into 30 ml silanized, autoclaved 30 ml Corex tubes with 15 ml QF buffer (50° C.). Isopropanol (10.5 ml) was added to each sample, the tubes covered with parafin and mixed by repeated inversion until the DNA precipitated. Samples were pelleted by centrifugation in the SS-34 rotor at 15,000 rpm for 10 minutes at 4° C. The pellet location was marked, the supernatant discarded, and 10 ml 70% ethanol (4° C.) was added. Samples were pelleted again by centrifugation on the SS-34 rotor at 10,000 rpm for 10 minutes at 4° C. The pellet location was marked and the supernatant discarded. The tubes were then placed on their side in a drying rack and dried 10 minutes at 37° C., taking care not to overdry the samples.

After drying, the pellets were dissolved into 1.0 ml TE (pH 8.5) and placed at 50° C. for 1-2 hours. Samples were held overnight at 4° C. as dissolution continued. The DNA solution was then transferred to 1.5 ml tubes with a 26 gauge needle on a tuberculin syringe. The transfer was repeated 5× in order to shear the DNA. Samples were then placed at 50° C. for 1-2 hours.

(2) Quantitation of Genomic DNA and Preparation for Gene Amplification Assay

The DNA levels in each tube were quantified by standard A₂₆₀, A₂₈₀ spectrophotometry on a 1:20 dilution (5 μl DNA+95 μl ddH₂O) using the 0.1 ml quartz cuvetts in the Beckman DU640 spectrophotometer. A₂₆₀/A₂₈₀ ratios were in the range of 1.8-1.9. Each DNA samples was then diluted further to approximately 200 ng/ml in TE (pH 8.5). If the original material was highly concentrated (about 700 ng/μl), the material was placed at 50° C. for several hours until resuspended.

Fluorometric DNA quantitation was then performed on the diluted material (20-600 ng/ml) using the manufacturer's guidelines as modified below. This was accomplished by allowing a Hoeffer DyNA Quant 200 fluorometer to warm-up for about 15 minutes. The Hoechst dye working solution (#H33258, 10 μl prepared within 12 hours of use) was diluted into 100 ml 1×TNE buffer. A 2 ml cuvette was filled with the fluorometer solution, placed into the machine, and the machine was zeroed. pGEM 3Zf(+) (2 μl, lot #360851026) was added to 2 ml of fluorometer solution and calibrated at 200 units. An additional 2 μl of pGEM 3Zf(+) DNA was then tested and the reading confirmed at 400 +/−10 units. Each sample was then read at least in triplicate. When 3 samples were found to be within 10% of each other, their average was taken and this value was used as the quantification value.

The fluorometricly determined concentration was then used to dilute each sample to 10 ng/μl in ddH₂O. This was done simultaneously on all template samples for a single TaqMan plate assay, and with enough material to run 500-1000 assays. The samples were tested in triplicate with Taqman™ primers and probe both B-actin and GAPDH on a single plate with normal human DNA and no-template controls. The diluted samples were used provided that the CT value of normal human DNA subtracted from test DNA was +/−1 Ct. The diluted, lot-qualified genomic DNA was stored in 1.0 ml aliquots at −80° C. Aliquots which were subsequently to be used in the gene amplification assay were stored at 4° C. Each 1 ml aliquot is enough for 8-9 plates or 64 tests

Gene Amplification Assay

The PRO polypeptide compounds of the invention were screened in the following primary tumors and the resulting ΔCt values greater than or equal to 1.0 are reported in Table 9 below.

TABLE 9 ΔCt values in lung and colon primary tumors and cell line models Primary Tumors or Cell PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- PRO- lines 187 533 214 343 211 230 246 317 232 269 304 339 LT7 1.52 1.04 1.08 LT13 2.74 1.85 2.71 1.88 3.42 1.63 1.90 1.27 1.29 1.04 2.98 1.83 2.23 2.26 3.22 1.68 2.24 2.44 2.84 2.93 2.15 2.75 2.53 1.82 LT3 1.57 1.97 1.06 1.86 1.17 LT4 1.17 1.18 LT9 1.42 1.04 1.80 1.03 LT12 2.70 1.38 2.23 1.51 2.86 1.54 2.54 2.40 1.14 1.15 1.26 2.90 1.49 1.50 1.27 2.96 2.47 1.74 2.27 2.92 1.25 2.68 2.28 1.34 LT30 1.67 2.13 1.36 LT21 1.26 1.09 1.50 LT1-a 1.02 1.18 1.29 LT6 1.93 LT10 1.96 1.07 2.57 LT11 1.09 1.67 1.00 2.05 1.32 3.43 2.20 1.14 1.51 1.39 1.80 1.89 1.14 1.41 2.33 1.54 1.02 LT15 3.75 1.77 3.62 2.44 4.32 2.11 2.06 1.86 1.36 1.34 3.92 1.58 1.30 2.16 4.47 1.56 2.76 3.49 3.64 1.63 2.94 3.56 3.32 2.68 LT16 2.10 1.66 1.70 1.25 1.15 1.55 1.00 2.04 1.08 1.83 1.33 LT17 1.32 1.93 1.15 1.85 1.26 2.68 2.29 1.35 1.42 1.68 1.63 1.87 2.30 1.39 1.69 2.03 1.30 1.10 1.33 1.30 LT18 1.17 1.04 LT19 4.05 1.67 2.09 3.82 2.42 4.05 1.91 2.51 1.21 1.60 1.15 3.99 1.98 2.55 4.92 1.68 2.03 4.93 1.16 3.78 4.76 HF-000840 1.58 Calu-1 1.08 SW900 1.86 CT2 3.56 2.49 1.95 1.42 2.75 3.49 2.36 CT3 2.06 1.15 1.34 CT8 1.01 1.48 1.29 1.58 CT10 1.81 1.84 1.88 1.00 1.88 1.49 1.55 CT12 1.81 1.74 1.13 CT14 1.82 2.48 2.33 1.36 1.72 1.24 CT15 1.63 2.06 1.33 1.41 1.04 CT16 1.95 1.78 1.40 CT17 2.04 2.40 1.74 CT1 1.24 1.22 1.27 1.25 2.41 1.34 1.46 1.14 CT4 1.36 1.77 1.33 1.32 1.10 1.17 2.05 1.42 1.02 CT5 2.96 1.56 2.68 1.76 2.27 1.33 1.59 2.99 2.76 1.64 2.39 CT6 1.10 1.33 1.01 1.14 CT7 1.40 1.66 1.39 1.00 CT9 1.39 1.16 1.09 1.24 1.13 CT11 2.22 2.05 1.55 2.01 1.75 1.48 1.92 2.26 1.85 1.83 1.12 HF000539 1.57 SW620 1.14 HF000611 4.64 HF000733 1.93 2.33 HF000716 1.68 2.82 CT18 1.29

Summary

Because amplification of the various DNA's as described above occurs in various tumors, it is likely associated with tumor formation and/or growth. As a result, antagonists (e.g., antibodies) directed against these polypeptides would be expected to be useful in cancer therapy.

Example 94 Detection of PRO Polypeptides That Affect Glucose or FFA Uptake by Primary Rat Adipocytes (Assay 94)

This assay is designed to determine whether PRO polypeptides show the ability to affect glucose or FFA uptake by adipocyte cells. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of disorders where either the stimulation or inhibition of glucose uptake by adipocytes would be beneficial including, for example, obesity, diabetes or hyper- or hypo-insulinemia.

In a 96 well format, PRO polypeptides to be assayed are added to primary rat adipocytes, and allowed to incubate overnight. Samples are taken at 4 and 16 hours and assayed for glycerol, glucose and FFA uptake. After the 16 hour incubation, insulin is added to the media and allowed to incubate for 4 hours. At this time, a sample is taken and glycerol, glucose and FFA uptake is measured. Media containing insulin without the PRO polypeptide is used as a positive reference control. As the PRO polypeptide being tested may either stimulate or inhibit glucose and FFA uptake, results are scored as positive in the assay if greater than 1.5 times or less than 0.5 times the insulin control.

The following PRO polypeptides tested positive as stimulators of glucose and/or FFA uptake in this assay: PRO221, PRO235, PRO245, PRO295, PRO301 and PRO332.

The following PRO polypeptides tested positive as inhibitors of glucose and/or FFA uptake in this assay: PRO214, PRO219, PRO228, PRO222, PRO231 and PRO265.

Example 95 Chondrocyte Re-differentiation Assay (Assay 110)

This assay shows that certain polypeptides of the invention act to induce redifferentiation of chondrocytes, therefore, are expected to be useful for the treatment of various bone and/or cartilage disorders such as, for example, sports injuries and arthritis. The assay is performed as follows. Porcine chondrocytes are isolated by overnight collagenase digestion of articulary cartilage of metacarpophalangeal joints of 4-6 month old female pigs. The isolated cells are then seeded at 25,000 cells/cm² in Ham F-12 containing 10% FBS and 4 μg/ml gentamycin. The culture media is changed every third day and the cells are then seeded in 96 well plates at 5,000 cells/well in 100 μl of the same media without serum and 100 μl of the test PRO polypeptide, 5 nM staurosporin (positive control) or medium alone (negative control) is added to give a final volume of 200 μl/well. After 5 days of incubation at 37° C., a picture of each well is taken and the differentiation state of the chondrocytes is determined. A positive result in the assay occurs when the redifferentiation of the chondrocytes is determined to be more similar to the positive control than the negative control.

The following polypeptide tested positive in this assay: PRO214, PRO219, PRO229, PRO222, PRO224, PRO230, PRO257, PRO272 and PRO301.

Example 96 Fetal Hemoglobin Induction in an Erythroblastic Cell Line (Assay 107)

This assay is useful for screening PRO polypeptides for the ability to induce the switch from adult hemoglobin to fetal hemoglobin in an erythroblastic cell line. Molecules testing positive in this assay are expected to be useful for therapeutically treating various mammalian hemoglobin-associated disorders such as the various thalassemias. The assay is performed as follows. Erythroblastic cells are plated in standard growth medium at 1000 cells/well in a 96 well format. PRO polypeptides are added to the growth medium at a concentration of 0.2% or 2% and the cells are incubated for 5 days at 37° C. As a positive control, cells are treated with 100μM hemin and as a negative control, the cells are untreated. After 5 days, cell lysates are prepared and analyzed for the expression of gamma globin (a fetal marker). A positive in the assay is a gamma globin level at least 2-fold above the negative control.

The following polypeptides tested positive in this assay: PRO221 and PRO245.

Example 97 Mouse Kidney Mesangial Cell Proliferation Assay (Assay 92)

This assay shows that certain polypeptides of the invention act to induce proliferation of mammalian kidney mesangial cells and, therefore, are useful for treating kidney disorders associated with decreased mesangial cell function such as Berger disease or other nephropathies associated with Schönlein-Henoch purpura, celiac disease, dermatitis herpetiformis or Crohn disease. The assay is performed as follows. On day one, mouse kidney mesangial cells are plated on a 96 well plate in growth media (3:1 mixture of Dulbecco's modified Eagle's medium and Ham's F12 medium, 95% fetal bovine serum, 5% supplemented with 14 mM HEPES) and grown overnight. On day 2, PRO polypeptides are diluted at 2 concentrations(1% and 0.1%) in serum-free medium and added to the cells. Control samples are serum-free medium alone. On day 4, 20 μl of the Cell Titer 96 Aqueous one solution reagent (Progema) was added to each well and the colormetric reaction was allowed to proceed for 2 hours. The absorbance (OD) is then measured at 490 nm. A positive in the assay is anything that gives an absorbance reading which is at least 15% above the control reading.

The following polypeptide tested positive in this assay: PRO227.

Example 98 Proliferation of Rat Utricular Supporting Cells (Assay 54)

This assay shows that certain polypeptides of the invention act as potent mitogens for inner ear supporting cells which are auditory hair cell progenitors and, therefore, are useful for inducing the regeneration of auditory hair cells and treating hearing loss in mammals. The assay is performed as follows. Rat UEC-4 utricular epithelial cells are aliquoted into 96 well plates with a density of 3000 cells/well in 200 μl of serum-containing medium at 33° C. The cells are cultured overnight and are then switched to serum-free medium at 37° C. Various dilutions of PRO polypeptides (or nothing for a control) are then added to the cultures and the cells are incubated for 24 hours. After the 24 hour incubation, ³H-thymidine (1 μCi/well) is added and the cells are then cultured for an additional 24 hours. The cultures are then washed to remove unincorporated radiolabel, the cells harvested and Cpm per well determined. Cpm of at least 30% or greater in the PRO polypeptide treated cultures as compared to the control cultures is considered a positive in the assay.

The following polypeptides tested positive in this assay: PRO310 and PRO346.

Example 99 Chondrocyte Proliferation Assay (Assay 111)

This assay is designed to determine whether PRO polypeptides of the present invention show the ability to induce the proliferation and/or redifferentiation of chondrocytes in culture. PRO polypeptides testing positive in this assay would be expected to be useful for the therapeutic treatment of various bone and/or cartilage disorders such as, for example, sports injuries and arthritis.

Porcine chondrocytes are isolated by overnight collagenase digestion of articular cartilage of the metacarpophalangeal joint of 4-6 month old female pigs. The isolated cells are then seeded at 25,000 cells/cm² in Ham F-12 containing 10% FBS and 4 μg/ml gentamycin. The culture media is changed every third day and the cells are reseeded to 25,000 cells/cm² every five days. On day 12, the cells are seeded in 96 well plates at 5,000 cells/well in 100 μl of the same media without serum and 100 μl of either serum-free medium (negative control), staurosporin (final concentration of 5 nM; positive control) or the test PRO polypeptide are added to give a final volume of 200 μl/well. After 5 days at 37° C., 20 μl of Alamar blue is added to each well and the plates are incubated for an additional 3 hours at 37° C. The fluorescence is then measured in each well (Ex:530 nm; Em: 590 nm). The fluorescence of a plate containing 200 μl of the serum-free medium is measured to obtain the background. A positive result in the assay is obtained when the fluorescence of the PRO polypeptide treated sample is more like that of the positive control than the negative control.

The following PRO polypeptides tested positive in this assay: PRO219, PRO222, PRO317, PRO257, PRO265, PRO287, PRO272 and PRO533.

Example 100 Inhibition of Heart Neonatal Hypertrophy Induced by LIF+ET-1 (Assay 74)

This assay is designed to determine whether PRO polypeptides of the present invention show the ability to inhibit neonatal heart hypertrophy induced by LIF and endothelin-1 (ET-1). A test compound that provides a positive response in the present assay would be useful for the therapeutic treatment of cardiac insufficiency diseases or disorders characterized or associated with an undesired hypertrophy of the cardiac muscle.

Cardiac myocytes from 1-day old Harlan Sprague Dawley rats (180 μl at 7.5×10⁴/ml, serum <0.1, freshly isolated) are introduced on day 1 to 96-well plates previously coated with DMEM/F12+4% FCS. Test PRO polypeptide samples or growth medium alone (negative control) are then added directly to the wells on day 2 in 20 μl volume. LIF+ET-1 are then added to the wells on day 3. The cells are stained after an additional 2 days in culture and are then scored visually the next day. A positive in the assay occurs when the PRO polypeptide treated myocytes are visually smaller on the average or less numerous than the untreated myocytes.

The following PRO polypeptides tested positive in this assay: PRO238.

Example 101 Tissue Expression Distribution

Oligonucleotide probes were constructed from some of the PRO polypeptide-encoding nucleotide sequences shown in the accompanying figures for use in quantitative PCR amplification reactions. The oligonucleotide probes were chosen so as to give an approximately 200-600 base pair amplified fragment from the 3′ end of its associated template in a standard PCR reaction. The oligonucleotide probes were employed in standard quantitative PCR amplification reactions with cDNA libraries isolated from different human adult and/or fetal tissue sources and analyzed by agarose gel electrophoresis so as to obtain a quantitative determination of the level of expression of the PRO polypeptide-encoding nucleic acid in the various tissues tested. Knowledge of the expression pattern or the differential expression of the PRO polypeptide-encoding nucleic acid in various different human tissue types provides a diagnostic marker useful for tissue typing, with or without other tissue-specific markers, for determining the primary tissue source of a metastatic tumor, and the like. These assays provided the following results.

Tissues With Tissues Lacking DNA Molecule Significant Expression Significant Expression DNA34436-1238 lung, placenta, brain testis DNA35557-1137 lung, kidney, brain placenta DNA35599-1168 kidney, brain liver, placenta DNA35668-1171 liver, lung, kidney placenta, brain DNA36992-1168 liver, lung, kidney, brain placenta DNA39423-1182 kidney, brain liver DNA40603-1232 liver brain, kidney, lung DNA40604-1187 liver brain, kidney, lung DNA41379-1236 lung, brain liver DNA33206-1165 heart, spleen, substantia nigra, dendrocytes hippocampus, cartilage, prostate, HUVEC DNA34431-1177 spleen, HUVEC, brain, colon tumor, cartilage, heart, uterus prostate, THP-1 macrophages DNA41225-1217 HUVEC, uterus, colon spleen, brain, heart, tumor, cartilage, prostate IM-9 lymphoblasts

Example 102 In situ Hybridization

In situ hybridization is a powerful and versatile technique for the detection and localization of nucleic acid sequences within cell or tissue preparations. It may be useful, for example, to identify sites of gene expression, analyze the tissue distribution of transcription, identify and localize viral infection, follow changes in specific mRNA synthesis and aid in chromosome mapping.

In situ hybridization was performed following an optimized version of the protocol by Lu and Gillett, Cell Vision 1:169-176 (1994), using PCR-generated ³³P-labeled riboprobes. Briefly, formalin-fixed, paraffin-embedded human tissues were sectioned, deparaffinized, deproteinated in proteinase K (20 g/ml) for 15 minutes at 37° C., and further processed for in situ hybridization as described by Lu and Gillett, supra. A [³³-P] UTP-labeled antisense riboprobe was generated from a PCR product and hybridized at 55° C. overnight. The slides were dipped in Kodak NTB2 nuclear track emulsion and exposed for 4 weeks.

³³P-Riboprobe Synthesis

6.0 μl (125 mCi) of ³³P-UTP (AmershamBF 1002, SA<2000 Ci/mmol) were speed vac dried. To each tube containing dried ³³P-UTP, the following ingredients were added:

2.0 μl 5×transcription buffer

1.0 μl DTT (100 mM)

2.0 μl NTP mix (2.5 mM: 10μ; each of 10 mM GTP, CTP & ATP+10 μl H₂O)

1.0 μl UTP (50 μM)

1.0 μl Rnasin

1.0 μl DNA template (1 μg)

1.0 μl H₂O

1.0 μl RNA polymerase (for PCR products T3=AS, T7=S, usually)

The tubes were incubated at 37° C. for one hour. 1.0 μl RQ1 DNase were added, followed by incubation at 37° C. for 15 minutes. 90 μl TE (10 mM Tris pH 7.6/1 mM EDTA pH 8.0) were added, and the mixture was pipetted onto DE81 paper. The remaining solution was loaded in a Microcon-50 ultrafiltration unit, and spun using program 10 (6 minutes). The filtration unit was inverted over a second tube and spun using program 2 (3 minutes). After the final recovery spin, 100 μl TE were added. 1 μl of the final product was pipetted on DE81 paper and counted in 6 ml of Biofluor II.

The probe was run on a TBE/urea gel. 1-3 μl of the probe or 5 μl of RNA Mrk III were added to 3 μl of loading buffer. After heating on a 95° C. heat block for three minutes, the gel was immediately placed on ice. The wells of gel were flushed, the sample loaded, and run at 180-250 volts for 45 minutes. The gel was wrapped in saran wrap and exposed to XAR film with an intensifying screen in −70° C. freezer one hour to overnight.

³³P-Hybridization

A. Pretreatment of Frozen Sections

The slides were removed from the freezer, placed on aluminium trays and thawed at room temperature for 5 minutes. The trays were placed in 55° C. incubator for five minutes to reduce condensation. The slides were fixed for 10 minutes in 4% paraformaldehyde on ice in the fume hood, and washed in 0.5×SSC for 5 minutes, at room temperature (25 ml 20'SSC+975 ml SQ H₂O). After deproteination in 0.5 μg/ml proteinase K for 10 minutes at 37° C. (12.5 μl of 10 mg/ml stock in 250 ml prewarmed RNase-free RNAse buffer), the sections were washed in 0.5×SSC for 10 minutes at room temperature. The sections were dehydrated in 70%, 95%, 100% ethanol, 2 minutes each.

B. Pretreatment of Paraffin-embedded Sections

The slides were deparaffinized, placed in SQ H₂O, and rinsed twice in 2×SSC at room temperature, for 5 minutes each time. The sections were deproteinated in 20 μg/ml proteinase K (500 μl of 10 mg/ml in 250 ml RNase-free RNase buffer; 37° C., 15 minutes)—human embryo, or 8×proteinase K (100 μl in 250 ml Rnase buffer, 37° C., 30 minutes)—formalin tissues. Subsequent rinsing in 0.5×SSC and dehydration were performed as described above.

C. Prehybridization

The slides were laid out in a plastic box lined with Box buffer (4×SSC, 50% formamide)—saturated filter paper. The tissue was covered with 50 μl of hybridization buffer (3.75 g Dextran Sulfate+6 ml SQ H₂O), vortexed and heated in the microwave for 2 minutes with the cap loosened. After cooling on ice, 18.75 ml formamide, 3.75 ml 20×SSC and 9 ml SQ H₂O were added, the tissue was vortexed well, and incubated at 42° C. for 1-4 hours.

D. Hybridization

1.0×10⁶ cpm probe and 1.0 μl tRNA (50 mg/ml stock) per slide were heated at 95° C. for 3 minutes The slides were cooled on ice, and 48 μl hybridization buffer were added per slide. After vortexing, 50 μl ³³P mix were added to 50 μl prehybridization on slide. The slides were incubated overnight at 55° C.

E. Washes

Washing was done 2×10 minutes with 2×SSC, EDTA at room temperature (400 ml 20×SSC+16 ml 0.25M EDTA, V_(f)=4L), followed by RNaseA treatment at 37° C. for 30 minutes (500 μl of 10 mg/ml in 250 ml Rnase buffer=20 μg/ml), The slides were washed 2×10 minutes with 2 ×SSC, EDTA at room temperature. The stringency wash conditions were as follows: 2 hours at 55° C., 0.1×SSC, EDTA (20 ml 20×SSC+16 ml EDTA, V_(f)=4L).

F. Oligonucleotides

In situ analysis was performed on a variety of DNA sequences disclosed herein. The oligonucleotides employed for these analyses are as follows.

(1) DNA33094-1131 (PRO217) p1 5′-GGATTCTAATACGACTCACTATAGGGCTCAGAAAAGCGCAACAGAGAA-3′ (SEQ ID NO:348) p2 5′-CTATGAAATTAACCCTCACTAAAGGGATGTCTTCCATGCCAACCTTC-3′ (SEQ ID NO:349) (2) DNA33223-1136 (PRO230) p1 5′-GGATTCTAATACGACTCACTATAGGGCGGCGATGTCCACTGGGGCTAC-3′ (SEQ ID NO:350) p2 5′-CTATGAAATTAACCCTCACTAAAGGGACGAGGAAGATGGGCGGATGGT-3′ (SEQ ID NO:351) (3) DNA34435-1140 (PRO232) p1 5′-GGATTCTAATACGACTCACTATAGGGCACCCACGCGTCCGGCTGCTT-3′ (SEQ ID NO:352) p2 5′-CTATGAAATTAACCCTCACTAAAGGGACGGGGGACACCACGGACCAGA-3′ (SEQ ID NO:353) (4) DNA35639-1172 (PRO246) p1 5′-GGATTCTAATACGACTCACTATAGGGCTTGCTGCGGTTTTTGTTCCTG-3′ (SEQ ID NO:354) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGCTGCCGATCCCACTGGTATT-3′ (SEQ ID NO:355) (5) DNA49435-1219 (PRO533) p1 5′-GGATTCTAATACGACTCACTATAGGGCGGATCCTGGCCGGCCTCTG-3′ (SEQ ID NO:356) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGCCCGGGCATGGTCTCAGTTA-3′ (SEQ ID NO:357) (6) DNA35638-1141 (PRO245) p1 5′-GGATTCTAATACGACTCACTATAGGGCGGGAAGATGGCGAGGAGGAG-3′ (SEQ ID NO:358) p2 5′-CTATGAAATTAACCCTCACTAAAGGGACCAAGGCCACAAACGGAAATC-3′ (SEQ ID NO:359) (7) DNA33089-1132 (PRO221) p1 5′-GGATTCTAATACGACTCACTATAGGGCTGTGCTTTCATTCTGCCAGTA-3′ (SEQ ID NO:360) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGGGTACAATTAAGGGGTGGAT-3′ (SEQ ID NO:361) (8) DNA35918-1174 (PRO258) p1 5′-GGATTCTAATACGACTCACTATAGGGCCCGCCTCGCTCCTGCTCCTG-3′ (SEQ ID NO:362) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGGATTGCCGCGACCCTCACAG-3′ (SEQ ID NO:363) (9) DNA32286-1191 (PRO214) p1 5′-GGATTCTAATACGACTCACTATAGGGCCCCTCCTGCCTTCCCTGTCC-3′ (SEQ ID NO:364) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGTGGTGGCCGCGATTATCTGC-3′ (SEQ ID NO:365) (10) DNA33221-1133 (PRO224) p1 5′-GGATTCTAATACGACTCACTATAGGGCGCAGCGATGGCAGCGATGAGG-3′ (SEQ ID NO:366) p2 5′-CTATGAAATTAACCCTCACTAAAGGGACAGACGGGGCAGAGGGAGTG-3′ (SEQ ID NO:367) (11) DNA35557-1137 (PRO234) p1 5′-GGATTCTAATACGACTCACTATAGGGCCAGGAGGCGTGAGGAGAAAC-3′ (SEQ ID NO:368) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAAAGACATGTCATCGGGAGTGG-3′ (SEQ ID NO:369) (12) DNA33100-1159 (PRO229) p1 5′-GGATTCTAATACGACTCACTATAGGGCCGGGTGGAGGTGGAACAGAAA-3′ (SEQ ID NO 370) p2 5′-CTATGAAATTAACCCTCACTAAAGGGACACAGACAGAGCCCCATACGC-3′ (SEQ ID NO 371) (13) DNA34431-1177 (PRO263) p1 5′-GGATTCTAATACGACTCACTATAGGGCCAGGGAAATCCGGATGTCTC-3′ (SEQ ID NO:372) p2 5′-CTATGAAATTAACCCTCACTAAAGGGAGTAAGGGGATGCCACCGAGTA-3′ (SEQ ID NO:373) (14) DNA38268-1188 (PRO295) p1 5′-GGATTCTAATACGACTCACTATAGGGCCAGCTACCCGCAGGAGGAGG-3′ (SEQ ID NO:374) p2 5′-CTATGAAATTAACCCTCACTAAAGGGATCCCAGGTGATGAGGTCCAGA-3′ (SEQ ID NO:375)

G. Results

In situ analysis was performed on a variety of DNA sequences disclosed herein. The results from these analyses are as follows.

(1) DNA33094-1131 (PRO217)

Highly distinctive expression pattern, that does not indicate an obvious biological function. In the human embryo it was expressed in outer smooth muscle layer of the GI tract, respiratiry cartilage, branching respiratory epithelium, osteoblasts, tendons, gonad, in the optic nerve head and developing dermis. In the adult expression was observed in the epidermal pegs of the chimp tongue, the basal epithelial/myoepithelial cells of the prostate and urinary bladder. Also expressed in the alveolar lining cells of the adult lung, mesenchymal cells juxtaposed to erectile tissue in the penis and the cerebral cortex (probably glial cells). In the kidney, expression was only seen in disease, in cells surrounding thyroidized renal tubules.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung, skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

(a) Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin, thymus, ovary, lymph node.

(b) Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(2) DNA33223-1136 (PRO230)

Sections show an intense signal associated with arterial and venous vessels in the fetus. In arteries the signal appeared to be confined to smooth-muscle/pericytic cells. The signal is also seen in capillary vessels and in glomeruli. It is not clear whether or not endothelial cells are expressing this mRNA. Expression is also observed in epithelial cells in the fetal lens. Strong expression was also seen in cells within placental trophoblastic villi, these cells lie between the trophoblast and the fibroblast-like cells that express HGF—uncertain histogenesis. In the adult, there was no evidence of expression and the wall of the aorta and most vessels appear to be negative. However, expression was seen over vascular channels in the normal prostate and in the epithelium lining the gallbladder. Insurers expression was seen in the vessels of the soft-tissue sarcoma and a renal cell carcinoma. In summary, this is a molecule that shows relatively specific vascular expression in the fetus as well as in some adult organs. Expression was also observed in the fetal lens and the adult gallbladder.

In a secondary screen, vascular expression was observed, similar to that observed above, seen in fetal blocks. Expression is on vascular smooth muscle, rather than endothelium. Expression also seen in smooth muscle of the developing oesophagus, so as reported previously, this molecule is not vascular specific. Expression was examined in 4 lung and 4 breast carcinomas. Substantial expression was seen in vascular smooth muscle of at least ¾ lung cancers and {fraction (2/4)} breast cancers. In addition, in one breast carcinoma, expression was observed in peritumoral stromal cells of uncertain histogenesis (possibly myofibroblasts). No endothelial cell expression was observed in this study.

(3) DNA34435-1140 (PRO232)

Strong expression in prostatic epithelium and bladder epithelium, lower level of expression in bronchial epithelium. High background/low level expression seen in a number of sites, including among others, bone, blood, chondrosarcoma, adult heart and fetal liver. It is felt that this level of signal represents background, partly because signal at this level was seen over the blood. All other tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

In a secondary screen, expression was observed in the epithelium of the prostate, the superficial layers of the urethelium of the urinary bladder, the urethelium lining the renal pelvis and the urethelium of the ureter (1 out of 2 experiments). The urethra of a rhesus monkey was negative; it is unclear whether this represents a true lack of expression by the urethra, or if it is the result of a failure of the probe to cross react with rhesus tissue. The findings in the prostate and bladder are similar to those previously described using an isotopic detection technique. Expression of the mRNA for this antigen is NOT prostate epithelial specific. The antigen may serve as a useful marker for urethelial derived tissues. Expression in the superficial, post-mitotic cells, of the urinary tract epithelium also suggest that it is unlikely to represent a specific stem cell marker, as this would be expected to be expressed specifically in basal epithelium.

(4) DNA35639-1172 (PRO246)

Strongly expressed in fetal vascular endothelium, including tissues of the CNS. Lower level of expression in adult vasculature, including the CNS. Not obviously expressed at higher levels in tumor vascular endothelium. Signal also seen over bone matrix and adult spleen, not obviously cell associated, probably related to non-specific background at these sites.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus

(5) DNA49435-1219 (PRO533)

Moderate expression over cortical neurones in the fetal brain. Expression over the inner aspect of the fetal retina, possible expression in the developing lens. Expression over fetal skin, cartilage, small intestine, placental villi and umbilical cord. In adult tissues there is an extremely high level of expression over the gallbladder epithelium. Moderate expression over the adult kidney, gastric and colonic epithelia. Low-level expression was observed over many cell types in many tissues, this may be related to stickiness of the probe, these data should therefore be interpreted with a degree of caution.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

(6) DNA35638-1141 (PRO245)

Expression observed in the endothelium lining a subset of fetal and placental vessels. Endothelial expression was confined to these tissue blocks. Expression also observed over intermediate trophoblast cells of placenta. Expression also observed tumor vasculature but not in the vasculature of normal tissues of the same type. All other tissues negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta, spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastric carcinoma, colon, colonic carcinoma, thyroid (chimp), parathyroid (chimp) ovary (chimp) and chondrosarcoma. Acetominophen induced liver injury and hepatic cirrhosis

(7) DNA33089-1132 (PRO221)

Specific expression over fetal cerebral white and grey matter, as well as over neurones in the spinal cord. Probe appears to cross react with rat. Low level of expression over cerebellar neurones in adult rhesus brain. All other tissues negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta, spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastric carcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominophen induced liver injury and hepatic cirrhosis

(8) DNA35918-1174 (PRO258)

Strong expression in the nervous system. In the rhesus monkey brain expression is observed in cortical, hippocampal and cerebellar neurones. Expression over spinal neurones in the fetal spinal cord, the developing brain and the inner aspects of the fetal retina. Expression over developing dorsal root and autonomic ganglia as well as enteric nerves. Expression observed over ganglion cells in the adult prostate. In the rat, there is strong expression over the developing hind brain and spinal cord. Strong expression over interstitial cells in the placental villi. All other tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, renal cell carcinoma, adrenal, aorta, spleen, lymph node, pancreas, lung, myocardium, skin, cerebral cortex (rm), hippocampus(rm), cerebellum(rm), bladder, prostate, stomach, gastric carcinoma, colon, colonic carcinoma, thyroid (chimp), parathyroid (chimp) ovary (chimp) and chondrosarcoma. Acetominophen induced liver injury and hepatic cirrhosis.

(9) DNA32286-1191 (PRO214)

Fetal tissue: Low level throughout mesenchyme. Moderate expression in placental stromal cells in membranous tissues and in thyroid. Low level expression in cortical neurones. Adult tissue: all negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined include: Liver, kidney, adrenal, myocardium, aorta, spleen, lymph node, pancreas, lung and skin.

(10) DNA33221-1133 (PRO224)

Expression limited to vascular endothelium in fetal spleen, adult spleen, fetal liver, adult thyroid and adult lymph node (chimp). Additional site of expression is the developing spinal ganglia. All other tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, myocardium, aorta, spleen, lymph node, pancreas, lung, skin, eye (inc. retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin, thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(11) DNA35557-1137 (PRO234)

Specific expression over developing motor neurones in ventral aspect of the fetal spinal cord (will develop into ventral horns of spinal cord). All other tissues negative. Possible role in growth, differentiation and/or development of spinal motor neurons.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, myocardium, aorta, spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm), cerebellum(rm), penis, eye, bladder, stomach, gastric carcinoma, colon, colonic carcinoma and chondrosarcoma. Acetominophen induced liver injury and hepatic cirrhosis

(12) DNA33100-1159 (PRO229)

Striking expression in mononuclear phagocytes (macrophages) of fetal and adult spleen, liver, lymph node and adult thymus (in tingible body macrophages). The highest expression is in the spleen. All other tissues negative. Localisation and homology are entirely consistent with a role as a scavenger receptor for cells of the reticuloendothelial system. Expression also observed in placental mononuclear cells.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, myocardium, aorta, spleen, lymph node, gall bladder, pancreas, lung, skin, eye (inc. retina), prostate, bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: Salivary gland, stomach, thyroid, parathyroid, skin, thymus, ovary, lymph node.

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum, penis.

(13) DNA34431-1177 (PRO263)

Widepread expression in human fetal tissues and placenta over mononuclear cells, probably macrophages +/− lymphocytes. The cellular distribution follows a perivascular pattern in many tissues. Strong expression also seen in epithelial cells of the fetal adrenal cortex. All adult tissues were negative.

Fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, heart, great vessels, oesophagus, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis and lower limb.

Adult tissues examined: Liver, kidney, adrenal, spleen, lymph node, pancreas, lung, skin, cerebral cortex (rm), hippocampus(rm), cerebellum(rm), bladder, stomach, colon and colonic carcinoma. Acetominophen induced liver injury and hepatic cirrhosis.

A secondary screen evidenced expression over stromal mononuclear cells probably histiocytes.

(14) DNA38268-1188 (PRO295)

High expression over ganglion cells in human fetal spinal ganglia and over large neurones in the anterior horns of the developing spinal cord. In the adult there is expression in the chimp adrenal medulla (neural), neurones of the rhesus monkey brain (hippocampus [+++] and cerebral cortex) and neurones in ganglia in the normal adult human prostate (the only section that contains ganglion cells, i.e. expression in this cell type is presumed NOT to be confined to the prostate). All other tissues negative.

Human fetal tissues examined (E12-E16 weeks) include: Placenta, umbilical cord, liver, kidney, adrenals, thyroid, lungs, great vessels, stomach, small intestine, spleen, thymus, pancreas, brain, eye, spinal cord, body wall, pelvis, testis and lower limb.

Adult human tissues examined: Kidney (normal and end-stage), adrenal, spleen, lymph node, pancreas, lung, eye (inc. retina), bladder, liver (normal, cirrhotic, acute failure).

Non-human primate tissues examined:

Chimp Tissues: adrenal

Rhesus Monkey Tissues: Cerebral cortex, hippocampus, cerebellum.

Example 103 Isolation of cDNA Clones Encoding Human PRO1868

A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA49803. Based up an observed homology between the DNA49803 consensus sequence and an EST sequence contained within the Incyte EST clone no. 2994689, Incyte EST clone no. 2994689 was purchased and its insert obtained and sequenced. The sequence of that insert is shown in FIG. 123 and is herein designated DNA77624-2515.

The entire nucleotide sequence of DNA77624-2515 is shown in FIG. 123 (SEQ ID NO:422). Clone DNA77624-2515 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 51-53 and ending at the stop codon at nucleotide positions 981-983 (FIG. 123). The predicted polypeptide precursor is 310 amino acids long (FIG. 124). The full-length PRO1868 protein shown in FIG. 124 has an estimated molecular weight of about 35,020 daltons and a pI of about 7.90. Analysis of the full-length PRO1868 sequence shown in FIG. 124 (SEQ ID NO:423) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 30, a transmembrane domain from about amino acid 243 to about amino acid 263, potential N-glycosylation sites from about amino acid 104 to about amino acid 107 and from about amino acid 192 to about amino acid 195, a cAMP- and cGMP-dependent protein kinase phosphorylation site from about amino acid 107 to about amino acid 110, casein kinase II phosphorylation sites from about amino acid 106 to about amino acid 109 and from about amino acid 296 to about amino acid 299, a tyrosine kinase phosphorylation site from about amino acid 69 to about amino acid 77 and potential N-myristolation sites from about amino acid 26 to about amino acid 31, from about amino acid 215 to about amino acid 220, from about amino acid 226 to about amino acid 231, from about amino acid 243 to about amino acid 248, from about amino acid 244 to about amino acid 249 and from about amino acid 262 to about amino acid 267. Clone DNA77624-2515 has been deposited with ATCC on Dec. 22, 1998 and is assigned ATCC deposit no. 203553.

An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 124 (SEQ ID NO:423), evidenced significant homology between the PRO1868 amino acid sequence and the following Dayhoff sequences: HGS_RC75, P_W61379, A33_HUMAN, P_W14146, P_W14158, AMAL_DROME, P_R77437, I38346, NCM2_HUMAN and PTPD_HUMAN.

Example 104 Identification of Receptor/Ligand Interactions

In this assay, various PRO polypeptides are tested for ability to bind to a panel of potential receptor molecules for the purpose of identifying receptor/ligand interactions. The identification of a ligand for a known receptor, a receptor for a known ligand or a novel receptor/ligand pair is useful for a variety of indications including, for example, targeting bioactive molecules (linked to the ligand or receptor) to a cell known to express the receptor or ligand, use of the receptor or ligand as a reagent to detect the presence of the ligand or receptor in a composition suspected of containing the same, wherein the composition may comprise cells suspected of expressing the ligand or receptor, modulating the growth of or another biological or immunological activity of a cell known to express or respond to the receptor or ligand, modulating the immune response of cells or toward cells that express the receptor or ligand, allowing the preparation of agonists, antagonists and/or antibodies directed against the receptor or ligand which will modulate the growth of or a biological or immunological activity of a cell expressing the receptor or ligand, and various other indications which will be readily apparent to the ordinarily skilled artisan.

The assay is performed as follows. A PRO polypeptide of the present invention suspected of being a ligand for a receptor is expressed as a fusion protein containing the Fc domain of human IgG (an immunoadhesin). Receptor-ligand binding is detected by allowing interaction of the immunoadhesin polypeptide with cells (e.g. Cos cells) expressing candidate PRO polypeptide receptors and visualization of bound immunoadhesin with fluorescent reagents directed toward the Fc fusion domain and examination by microscope. Cells expressing candidate receptors are produced by transient transfection, in parallel, of defined subsets of a library of cDNA expression vectors encoding PRO polypeptides that may function as receptor molecules. Cells are then incubated for 1 hour in the presence of the PRO polypeptide immunoadhesin being tested for possible receptor binding. The cells are then washed and fixed with paraformaldehyde. The cells are then incubated with fluorescent conjugated antibody directed against the Fc portion of the PRO polypeptide immunoadhesin (e.g. FITC conjugated goat anti-human-Fc antibody). The cells are then washed again and examined by microscope. A positive interaction is judged by the presence of fluorescent labeling of cells transfected with cDNA encoding a particular PRO polypeptide receptor or pool of receptors and an absence of similar fluorescent labeling of similarly prepared cells that have been transfected with other cDNA or pools of cDNA. If a defined pool of cDNA expression vectors is judged to be positive for interaction with a PRO polypeptide immunoadhesin, the individual cDNA species that comprise the pool are tested individually (the pool is “broken down ”) to determine the specific cDNA that encodes a receptor able to interact with the PRO polypeptide immunoadhesin.

In another embodiment of this assay, an epitope-tagged potential ligand PRO polypeptide (e.g. 8 histidine “His ” tag) is allowed to interact with a panel of potential receptor PRO polypeptide molecules that have been expressed as fusions with the Fc domain of human IgG (immunoadhesins). Following a 1 hour co-incubation with the epitope tagged PRO polypeptide, the candidate receptors are each immunoprecipitated with protein A beads and the beads are washed. Potential ligand interaction is determined by western blot analysis of the immunoprecipitated complexes with antibody directed towards the epitope tag. An interaction is judged to occur if a band of the anticipated molecular weight of the epitope tagged protein is observed in the western blot analysis with a candidate receptor, but is not observed to occur with the other members of the panel of potential receptors.

Using these assays, the following receptor/ligand interactions have been herein identified: PRO245 binds to PRO1868.

Deposit of Material

The following materials have been deposited with the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. U.S.A. (ATCC):

Material ATCC Dep. No. Deposit Date DNA32292-1131 ATCC 209258 Sep. 16, 1997 DNA33094-1131 ATCC 209256 Sep. 16, 1997 DNA33223-1136 ATCC 209264 Sep. 16, 1997 DNA34435-1140 ATCC 209250 Sep. 16, 1997 DNA27864-1155 ATCC 209375 Oct. 16, 1997 DNA36350-1158 ATCC 209378 Oct. 16, 1997 DNA32290-1164 ATCC 209384 Oct. 16, 1997 DNA35639-1172 ATCC 209396 Oct. 17, 1997 DNA33092-1202 ATCC 209420 Oct. 28, 1997 DNA49435-1219 ATCC 209480 Nov. 21, 1997 DNA35638-1141 ATCC 209265 Sep. 16, 1997 DNA32298-1132 ATCC 209257 Sep. 16, 1997 DNA33089-1132 ATCC 209262 Sep. 16, 1997 DNA33786-1132 ATCC 209253 Sep. 16, 1997 DNA35918-1174 ATCC 209402 Oct. 17, 1997 DNA37150-1178 ATCC 209401 Oct. 17, 1997 DNA38260-1180 ATCC 209397 Oct. 17, 1997 DNA39969-1185 ATCC 209400 Oct. 17, 1997 DNA32286-1191 ATCC 209385 Oct. 16, 1997 DNA33461-1199 ATCC 209367 Oct. 15, 1997 DNA40628-1216 ATCC 209432 Nov. 7, 1997 DNA33221-1133 ATCC 209263 Sep. 16, 1997 DNA33107-1135 ATCC 209251 Sep. 16, 1997 DNA35557-1137 ATCC 209255 Sep. 16, 1997 DNA34434-1139 ATCC 209252 Sep. 16, 1997 DNA33100-1159 ATCC 209373 Oct. 16, 1997 DNA35600-1162 ATCC 209370 Oct. 16, 1997 DNA34436-1238 ATCC 209523 Dec. 10, 1997 DNA33206-1165 ATCC 209372 Oct. 16, 1997 DNA35558-1167 ATCC 209374 Oct. 16, 1997 DNA35599-1168 ATCC 209373 Oct. 16, 1997 DNA36992-1168 ATCC 209382 Oct. 16, 1997 DNA34407-1169 ATCC 209383 Oct. 16, 1997 DNA35841-1173 ATCC 209403 Oct. 17, 1997 DNA33470-1175 ATCC 209398 Oct. 17, 1997 DNA34431-1177 ATCC 209399 Oct. 17, 1997 DNA39510-1181 ATCC 209392 Oct. 17, 1997 DNA39423-1182 ATCC 209387 Oct. 17, 1997 DNA40620-1183 ATCC 209388 Oct. 17, 1997 DNA40604-1187 ATCC 209394 Oct. 17, 1997 DNA38268-1188 ATCC 209421 Oct. 28, 1997 DNA37151-1193 ATCC 209393 Oct. 17, 1997 DNA35673-1201 ATCC 209418 Oct. 28, 1997 DNA40370-1217 ATCC 209485 Nov. 21, 1997 DNA42551-1217 ATCC 209483 Nov. 21, 1997 DNA39520-1217 ATCC 209482 Nov. 21, 1997 DNA41225-1217 ATCC 209491 Nov. 21, 1997 DNA43318-1217 ATCC 209481 Nov. 21, 1997 DNA40587-1231 ATCC 209438 Nov. 7, 1997 DNA41338-1234 ATCC 209927 Jun. 2, 1998 DNA40981-1234 ATCC 209439 Nov. 7, 1997 DNA37140-1234 ATCC 209489 Nov. 21, 1997 DNA40982-1235 ATCC 209433 Nov. 7, 1997 DNA41379-1236 ATCC 209488 Nov. 21, 1997 DNA44167-1243 ATCC 209434 Nov. 7, 1997 DNA39427-1179 ATCC 209395 Oct. 17, 1997 DNA40603-1232 ATCC 209486 Nov. 21, 1997 DNA43466-1225 ATCC 209490 Nov. 21, 1997 DNA43046-1225 ATCC 209484 Nov. 21, 1997 DNA35668-1171 ATCC 209371 Oct. 16, 1997 DNA77624-2515 ATCC 203553 Dec. 22, 1998

These deposit were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations there under (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The deposits will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Genentech, Inc. and ATCC, which assures that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of the pertinent U.S. patent, assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 USC §122 and the Commissioner's rules pursuant thereto (including 37 CFR §1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.

The foregoing written specification is considered to be sufficient to enable one skilled in the art to practice the invention. The present invention is not to be limited in scope by the construct deposited, since the deposited embodiment is intended as a single illustration of certain aspects of the invention and any constructs that are functionally equivalent are within the scope of this invention. The deposit of material herein does not constitute an admission that the written description herein contained is inadequate to enable the practice of any aspect of the invention, including the best mode thereof, nor is it to be construed as limiting the scope of the claims to the specific illustrations that it represents. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the appended claims.

APPENDIX A I hereby claim benefit under Title 35, United States Code, §119(e) of any United States Provisional applications listed below: Provisional Application Ser. No. Filing Date 60/059,115 Sep. 17, 1997 60/059,184 Sep. 17, 1997 60/059,122 Sep. 17, 1997 60/059,117 Sep. 17, 1997 60/059,113 Sep. 17, 1997 60/059,121 Sep. 17, 1997 60/059,119 Sep. 17, 1997 60/059,263 Sep. 18, 1997 60/059,266 Sep. 18, 1997 60/062,125 Oct. 15, 1997 60/062,287 Oct. 17, 1997 60/062,285 Oct. 17, 1997 60/063,486 Oct. 21, 1997 60/062,816 Oct. 24, 1997 60/062,814 Oct. 24, 1997 60/063,127 Oct. 24, 1997 60/063,120 Oct. 24, 1997 60/063,121 Oct. 24, 1997 60/063,045 Oct. 24, 1997 60/063,128 Oct. 24, 1997 60/063,329 Oct. 27, 1997 60/063,327 Oct. 27, 1997 60/063,549 Oct. 28, 1997 60/063,541 Oct. 28, 1997 60/063,550 Oct. 28, 1997 60/063,542 Oct. 28, 1997 60/063,544 Oct. 28, 1997 60/063,564 Oct. 28, 1997 60/063,734 Oct. 29, 1997 60/063,738 Oct. 29, 1997 60/063,704 Oct. 29, 1997 60/063,435 Oct. 29, 1997 60/064,215 Oct. 29, 1997 60/063,735 Oct. 29, 1997 60/063,732 Oct. 29, 1997 60/064,103 Oct. 31, 1997 60/063,870 Oct. 31, 1997 60/064,248 Nov. 3, 1997 60/064,809 Nov. 7, 1997 60/065,846 Nov. 11, 1997 60/065,186 Nov. 12, 1997 60/065,846 Nov. 17, 1997 60/065,693 Nov. 18, 1997 60/066,120 Nov. 21, 1997 60/066,364 Nov. 21, 1997 60/066,772 Nov. 24, 1997 60/066,466 Nov. 24, 1997 60/066,770 Nov. 24, 1997 60/066,511 Nov. 24, 1997 60/066,453 Nov. 24, 1997 60/066,840 Nov. 25, 1997 60/069,425 Dec. 12, 1997 60/088,026 Jun. 4, 1998 60/099,803 Sep. 10, 1998 60/100,262 Sep. 14, 1998 60/100,858 Sep. 17, 1998 60/104,080 Oct. 13, 1998 60/109,304 Nov. 20, 1998 60/113,296 Dec. 22, 1998 60/143,048 Jul. 7, 1999 60/145,698 Jul. 26, 1999 60/146,222 Jul. 28, 1999

APPENDIX B I hereby claim benefit under Title 35, United States Code, §120 of any United States Provisional applications listed below: PCT/US Ser. No. Filed Status PCT/US98/18824 Sep. 10, 1998 Abandoned PCT/US98/19177 Sep. 14, 1998 Abandoned PCT/US98/19330 Sep. 16, 1998 Abandoned PCT/US98/19437 Sep. 17, 1998 Abandoned PCT/US98/25108 Dec. 1, 1998 Abandoned PCT/US99/20594 Sep. 8, 1999 Pending PCT/US99/20944 Sep. 13, 1999 Pending PCT/US99/21090 Sep. 15, 1999 Pending PCT/US99/21547 Sep. 15, 1999 Pending PCT/US99/23089 Oct. 5, 1999 Pending PCT/US99/28214 Nov. 29,1999 Pending PCT/US99/28313 Nov. 30, 1999 Pending PCT/US99/28301 Dec. 1, 1999 Abandoned PCT/US99/28564 Dec. 2, 1999 Pending PCT/US99/28565 Dec. 2,1999 Pending PCT/US99/30095 Dec. 16, 1999 Pending PCT/US99/30999 Dec. 20, 1999 Pending PCT/US99/30911 Dec. 20, 1999 Pending PCT/US00/00219 Jan. 5, 2000 Pending PCT/US00/03565 Feb. 11, 2000 Pending PCT/US00/04414 Feb. 22, 2000 Pending PCT/US00/05004 Feb. 24, 2000 Pending PCT/US00/05841 Mar. 2, 2000 Pending PCT/US00/07377 Mar. 20, 2000 Pending PCT/US00/08439 Mar. 30, 2000 Pending PCT/US00/14042 May 22, 2000 Pending PCT/US00/15264 Jun. 2, 2000 Pending PCT/US00/20710 Jul. 28, 2000 Pending PCT/US00/23328 Aug. 24, 2000 Pending

                   #             SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 423 <210> SEQ ID NO 1 <211> LENGTH: 1825 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 actgcacctc ggttctatcg attgaattcc ccggggatcc tctagagatc cc #tcgacctc     60 gacccacgcg tccgggccgg agcagcacgg ccgcaggacc tggagctccg gc #tgcgtctt    120 cccgcagcgc tacccgccat gcgcctgccg cgccgggccg cgctggggct cc #tgccgctt    180 ctgctgctgc tgccgcccgc gccggaggcc gccaagaagc cgacgccctg cc #accggtgc    240 cgggggctgg tggacaagtt taaccagggg atggtggaca ccgcaaagaa ga #actttggc    300 ggcgggaaca cggcttggga ggaaaagacg ctgtccaagt acgagtccag cg #agattcgc    360 ctgctggaga tcctggaggg gctgtgcgag agcagcgact tcgaatgcaa tc #agatgcta    420 gaggcgcagg aggagcacct ggaggcctgg tggctgcagc tgaagagcga at #atcctgac    480 ttattcgagt ggttttgtgt gaagacactg aaagtgtgct gctctccagg aa #cctacggt    540 cccgactgtc tcgcatgcca gggcggatcc cagaggccct gcagcgggaa tg #gccactgc    600 agcggagatg ggagcagaca gggcgacggg tcctgccggt gccacatggg gt #accagggc    660 ccgctgtgca ctgactgcat ggacggctac ttcagctcgc tccggaacga ga #cccacagc    720 atctgcacag cctgtgacga gtcctgcaag acgtgctcgg gcctgaccaa ca #gagactgc    780 ggcgagtgtg aagtgggctg ggtgctggac gagggcgcct gtgtggatgt gg #acgagtgt    840 gcggccgagc cgcctccctg cagcgctgcg cagttctgta agaacgccaa cg #gctcctac    900 acgtgcgaag agtgtgactc cagctgtgtg ggctgcacag gggaaggccc ag #gaaactgt    960 aaagagtgta tctctggcta cgcgagggag cacggacagt gtgcagatgt gg #acgagtgc   1020 tcactagcag aaaaaacctg tgtgaggaaa aacgaaaact gctacaatac tc #cagggagc   1080 tacgtctgtg tgtgtcctga cggcttcgaa gaaacggaag atgcctgtgt gc #cgccggca   1140 gaggctgaag ccacagaagg agaaagcccg acacagctgc cctcccgcga ag #acctgtaa   1200 tgtgccggac ttacccttta aattattcag aaggatgtcc cgtggaaaat gt #ggccctga   1260 ggatgccgtc tcctgcagtg gacagcggcg gggagaggct gcctgctctc ta #acggttga   1320 ttctcatttg tcccttaaac agctgcattt cttggttgtt cttaaacaga ct #tgtatatt   1380 ttgatacagt tctttgtaat aaaattgacc attgtaggta atcaggagga aa #aaaaaaaa   1440 aaaaaaaaaa aaagggcggc cgcgactcta gagtcgacct gcagaagctt gg #ccgccatg   1500 gcccaacttg tttattgcag cttataatgg ttacaaataa agcaatagca tc #acaaattt   1560 cacaaataaa gcattttttt cactgcattc tagttgtggt ttgtccaaac tc #atcaatgt   1620 atcttatcat gtctggatcg ggaattaatt cggcgcagca ccatggcctg aa #ataacctc   1680 tgaaagagga acttggttag gtaccttctg aggcggaaag aaccagctgt gg #aatgtgtg   1740 tcagttaggg tgtggaaagt ccccaggctc cccagcaggc agaagtatgc aa #gcatgcat   1800 ctcaattagt cagcaaccca gtttt           #                   #             1825 <210> SEQ ID NO 2 <211> LENGTH: 353 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Arg Leu Pro Arg Arg Ala Ala Leu Gly Le #u Leu Pro Leu Leu Leu   1               5  #                 10  #                 15 Leu Leu Pro Pro Ala Pro Glu Ala Ala Lys Ly #s Pro Thr Pro Cys His              20      #             25      #             30 Arg Cys Arg Gly Leu Val Asp Lys Phe Asn Gl #n Gly Met Val Asp Thr          35          #         40          #         45 Ala Lys Lys Asn Phe Gly Gly Gly Asn Thr Al #a Trp Glu Glu Lys Thr      50              #     55              #     60 Leu Ser Lys Tyr Glu Ser Ser Glu Ile Arg Le #u Leu Glu Ile Leu Glu  65                  # 70                  # 75                  # 80 Gly Leu Cys Glu Ser Ser Asp Phe Glu Cys As #n Gln Met Leu Glu Ala                  85  #                 90  #                 95 Gln Glu Glu His Leu Glu Ala Trp Trp Leu Gl #n Leu Lys Ser Glu Tyr             100       #           105       #           110 Pro Asp Leu Phe Glu Trp Phe Cys Val Lys Th #r Leu Lys Val Cys Cys         115           #       120           #       125 Ser Pro Gly Thr Tyr Gly Pro Asp Cys Leu Al #a Cys Gln Gly Gly Ser     130               #   135               #   140 Gln Arg Pro Cys Ser Gly Asn Gly His Cys Se #r Gly Asp Gly Ser Arg 145                 1 #50                 1 #55                 1 #60 Gln Gly Asp Gly Ser Cys Arg Cys His Met Gl #y Tyr Gln Gly Pro Leu                 165   #               170   #               175 Cys Thr Asp Cys Met Asp Gly Tyr Phe Ser Se #r Leu Arg Asn Glu Thr             180       #           185       #           190 His Ser Ile Cys Thr Ala Cys Asp Glu Ser Cy #s Lys Thr Cys Ser Gly         195           #       200           #       205 Leu Thr Asn Arg Asp Cys Gly Glu Cys Glu Va #l Gly Trp Val Leu Asp     210               #   215               #   220 Glu Gly Ala Cys Val Asp Val Asp Glu Cys Al #a Ala Glu Pro Pro Pro 225                 2 #30                 2 #35                 2 #40 Cys Ser Ala Ala Gln Phe Cys Lys Asn Ala As #n Gly Ser Tyr Thr Cys                 245   #               250   #               255 Glu Glu Cys Asp Ser Ser Cys Val Gly Cys Th #r Gly Glu Gly Pro Gly             260       #           265       #           270 Asn Cys Lys Glu Cys Ile Ser Gly Tyr Ala Ar #g Glu His Gly Gln Cys         275           #       280           #       285 Ala Asp Val Asp Glu Cys Ser Leu Ala Glu Ly #s Thr Cys Val Arg Lys     290               #   295               #   300 Asn Glu Asn Cys Tyr Asn Thr Pro Gly Ser Ty #r Val Cys Val Cys Pro 305                 3 #10                 3 #15                 3 #20 Asp Gly Phe Glu Glu Thr Glu Asp Ala Cys Va #l Pro Pro Ala Glu Ala                 325   #               330   #               335 Glu Ala Thr Glu Gly Glu Ser Pro Thr Gln Le #u Pro Ser Arg Glu Asp             340       #           345       #           350 Leu <210> SEQ ID NO 3 <211> LENGTH: 2206 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 caggtccaac tgcacctcgg ttctatcgat tgaattcccc ggggatcctc ta #gagatccc     60 tcgacctcga cccacgcgtc cgccaggccg ggaggcgacg cgcccagccg tc #taaacggg    120 aacagccctg gctgagggag ctgcagcgca gcagagtatc tgacggcgcc ag #gttgcgta    180 ggtgcggcac gaggagtttt cccggcagcg aggaggtcct gagcagcatg gc #ccggagga    240 gcgccttccc tgccgccgcg ctctggctct ggagcatcct cctgtgcctg ct #ggcactgc    300 gggcggaggc cgggccgccg caggaggaga gcctgtacct atggatcgat gc #tcaccagg    360 caagagtact cataggattt gaagaagata tcctgattgt ttcagagggg aa #aatggcac    420 cttttacaca tgatttcaga aaagcgcaac agagaatgcc agctattcct gt #caatatcc    480 attccatgaa ttttacctgg caagctgcag ggcaggcaga atacttctat ga #attcctgt    540 ccttgcgctc cctggataaa ggcatcatgg cagatccaac cgtcaatgtc cc #tctgctgg    600 gaacagtgcc tcacaaggca tcagttgttc aagttggttt cccatgtctt gg #aaaacagg    660 atggggtggc agcatttgaa gtggatgtga ttgttatgaa ttctgaaggc aa #caccattc    720 tccaaacacc tcaaaatgct atcttcttta aaacatgtca acaagctgag tg #cccaggcg    780 ggtgccgaaa tggaggcttt tgtaatgaaa gacgcatctg cgagtgtcct ga #tgggttcc    840 acggacctca ctgtgagaaa gccctttgta ccccacgatg tatgaatggt gg #actttgtg    900 tgactcctgg tttctgcatc tgcccacctg gattctatgg agtgaactgt ga #caaagcaa    960 actgctcaac cacctgcttt aatggaggga cctgtttcta ccctggaaaa tg #tatttgcc   1020 ctccaggact agagggagag cagtgtgaaa tcagcaaatg cccacaaccc tg #tcgaaatg   1080 gaggtaaatg cattggtaaa agcaaatgta agtgttccaa aggttaccag gg #agacctct   1140 gttcaaagcc tgtctgcgag cctggctgtg gtgcacatgg aacctgccat ga #acccaaca   1200 aatgccaatg tcaagaaggt tggcatggaa gacactgcaa taaaaggtac ga #agccagcc   1260 tcatacatgc cctgaggcca gcaggcgccc agctcaggca gcacacgcct tc #acttaaaa   1320 aggccgagga gcggcgggat ccacctgaat ccaattacat ctggtgaact cc #gacatctg   1380 aaacgtttta agttacacca agttcatagc ctttgttaac ctttcatgtg tt #gaatgttc   1440 aaataatgtt cattacactt aagaatactg gcctgaattt tattagcttc at #tataaatc   1500 actgagctga tatttactct tccttttaag ttttctaagt acgtctgtag ca #tgatggta   1560 tagattttct tgtttcagtg ctttgggaca gattttatat tatgtcaatt ga #tcaggtta   1620 aaattttcag tgtgtagttg gcagatattt tcaaaattac aatgcattta tg #gtgtctgg   1680 gggcagggga acatcagaaa ggttaaattg ggcaaaaatg cgtaagtcac aa #gaatttgg   1740 atggtgcagt taatgttgaa gttacagcat ttcagatttt attgtcagat at #ttagatgt   1800 ttgttacatt tttaaaaatt gctcttaatt tttaaactct caatacaata ta #ttttgacc   1860 ttaccattat tccagagatt cagtattaaa aaaaaaaaaa ttacactgtg gt #agtggcat   1920 ttaaacaata taatatattc taaacacaat gaaataggga atataatgta tg #aacttttt   1980 gcattggctt gaagcaatat aatatattgt aaacaaaaca cagctcttac ct #aataaaca   2040 ttttatactg tttgtatgta taaaataaag gtgctgcttt agttttttgg aa #aaaaaaaa   2100 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa gggcggccgc gactctagag tc #gacctgca   2160 gaagcttggc cgccatggcc caacttgttt attgcagctt ataatg    #               2206 <210> SEQ ID NO 4 <211> LENGTH: 379 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Ala Arg Arg Ser Ala Phe Pro Ala Ala Al #a Leu Trp Leu Trp Ser   1               5  #                 10  #                 15 Ile Leu Leu Cys Leu Leu Ala Leu Arg Ala Gl #u Ala Gly Pro Pro Gln              20      #             25      #             30 Glu Glu Ser Leu Tyr Leu Trp Ile Asp Ala Hi #s Gln Ala Arg Val Leu          35          #         40          #         45 Ile Gly Phe Glu Glu Asp Ile Leu Ile Val Se #r Glu Gly Lys Met Ala      50              #     55              #     60 Pro Phe Thr His Asp Phe Arg Lys Ala Gln Gl #n Arg Met Pro Ala Ile  65                  # 70                  # 75                  # 80 Pro Val Asn Ile His Ser Met Asn Phe Thr Tr #p Gln Ala Ala Gly Gln                  85  #                 90  #                 95 Ala Glu Tyr Phe Tyr Glu Phe Leu Ser Leu Ar #g Ser Leu Asp Lys Gly             100       #           105       #           110 Ile Met Ala Asp Pro Thr Val Asn Val Pro Le #u Leu Gly Thr Val Pro         115           #       120           #       125 His Lys Ala Ser Val Val Gln Val Gly Phe Pr #o Cys Leu Gly Lys Gln     130               #   135               #   140 Asp Gly Val Ala Ala Phe Glu Val Asp Val Il #e Val Met Asn Ser Glu 145                 1 #50                 1 #55                 1 #60 Gly Asn Thr Ile Leu Gln Thr Pro Gln Asn Al #a Ile Phe Phe Lys Thr                 165   #               170   #               175 Cys Gln Gln Ala Glu Cys Pro Gly Gly Cys Ar #g Asn Gly Gly Phe Cys             180       #           185       #           190 Asn Glu Arg Arg Ile Cys Glu Cys Pro Asp Gl #y Phe His Gly Pro His         195           #       200           #       205 Cys Glu Lys Ala Leu Cys Thr Pro Arg Cys Me #t Asn Gly Gly Leu Cys     210               #   215               #   220 Val Thr Pro Gly Phe Cys Ile Cys Pro Pro Gl #y Phe Tyr Gly Val Asn 225                 2 #30                 2 #35                 2 #40 Cys Asp Lys Ala Asn Cys Ser Thr Thr Cys Ph #e Asn Gly Gly Thr Cys                 245   #               250   #               255 Phe Tyr Pro Gly Lys Cys Ile Cys Pro Pro Gl #y Leu Glu Gly Glu Gln             260       #           265       #           270 Cys Glu Ile Ser Lys Cys Pro Gln Pro Cys Ar #g Asn Gly Gly Lys Cys         275           #       280           #       285 Ile Gly Lys Ser Lys Cys Lys Cys Ser Lys Gl #y Tyr Gln Gly Asp Leu     290               #   295               #   300 Cys Ser Lys Pro Val Cys Glu Pro Gly Cys Gl #y Ala His Gly Thr Cys 305                 3 #10                 3 #15                 3 #20 His Glu Pro Asn Lys Cys Gln Cys Gln Glu Gl #y Trp His Gly Arg His                 325   #               330   #               335 Cys Asn Lys Arg Tyr Glu Ala Ser Leu Ile Hi #s Ala Leu Arg Pro Ala             340       #           345       #           350 Gly Ala Gln Leu Arg Gln His Thr Pro Ser Le #u Lys Lys Ala Glu Glu         355           #       360           #       365 Arg Arg Asp Pro Pro Glu Ser Asn Tyr Ile Tr #p     370               #   375 <210> SEQ ID NO 5 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 5 agggagcacg gacagtgtgc agatgtggac gagtgctcac tagca    #                   #45 <210> SEQ ID NO 6 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 6 agagtgtatc tctggctacg c            #                   #                   #21 <210> SEQ ID NO 7 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 7 taagtccggc acattacagg tc            #                   #                 22 <210> SEQ ID NO 8 <211> LENGTH: 49 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 8 cccacgatgt atgaatggtg gactttgtgt gactcctggt ttctgcatc   #               49 <210> SEQ ID NO 9 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 9 aaagacgcat ctgcgagtgt cc            #                   #                 22 <210> SEQ ID NO 10 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 10 tgctgatttc acactgctct ccc            #                   #                23 <210> SEQ ID NO 11 <211> LENGTH: 2197 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 cggacgcgtg ggcgtccggc ggtcgcagag ccaggaggcg gaggcgcgcg gg #ccagcctg     60 ggccccagcc cacaccttca ccagggccca ggagccacca tgtggcgatg tc #cactgggg    120 ctactgctgt tgctgccgct ggctggccac ttggctctgg gtgcccagca gg #gtcgtggg    180 cgccgggagc tagcaccggg tctgcacctg cggggcatcc gggacgcggg ag #gccggtac    240 tgccaggagc aggacctgtg ctgccgcggc cgtgccgacg actgtgccct gc #cctacctg    300 ggcgccatct gttactgtga cctcttctgc aaccgcacgg tctccgactg ct #gccctgac    360 ttctgggact tctgcctcgg cgtgccaccc ccttttcccc cgatccaagg at #gtatgcat    420 ggaggtcgta tctatccagt cttgggaacg tactgggaca actgtaaccg tt #gcacctgc    480 caggagaaca ggcagtggca tggtggatcc agacatgatc aaagccatca ac #cagggcaa    540 ctatggctgg caggctggga accacagcgc cttctggggc atgaccctgg at #gagggcat    600 tcgctaccgc ctgggcacca tccgcccatc ttcctcggtc atgaacatgc at #gaaattta    660 tacagtgctg aacccagggg aggtgcttcc cacagccttc gaggcctctg ag #aagtggcc    720 caacctgatt catgagcctc ttgaccaagg caactgtgca ggctcctggg cc #ttctccac    780 agcagctgtg gcatccgatc gtgtctcaat ccattctctg ggacacatga cg #cctgtcct    840 gtcgccccag aacctgctgt cttgtgacac ccaccagcag cagggctgcc gc #ggtgggcg    900 tctcgatggt gcctggtggt tcctgcgtcg ccgaggggtg gtgtctgacc ac #tgctaccc    960 cttctcgggc cgtgaacgag acgaggctgg ccctgcgccc ccctgtatga tg #cacagccg   1020 agccatgggt cggggcaagc gccaggccac tgcccactgc cccaacagct at #gttaataa   1080 caatgacatc taccaggtca ctcctgtcta ccgcctcggc tccaacgaca ag #gagatcat   1140 gaaggagctg atggagaatg gccctgtcca agccctcatg gaggtgcatg ag #gacttctt   1200 cctatacaag ggaggcatct acagccacac gccagtgagc cttgggaggc ca #gagagata   1260 ccgccggcat gggacccact cagtcaagat cacaggatgg ggagaggaga cg #ctgccaga   1320 tggaaggacg ctcaaatact ggactgcggc caactcctgg ggcccagcct gg #ggcgagag   1380 gggccacttc cgcatcgtgc gcggcgtcaa tgagtgcgac atcgagagct tc #gtgctggg   1440 cgtctggggc cgcgtgggca tggaggacat gggtcatcac tgaggctgcg gg #caccacgc   1500 ggggtccggc ctgggatcca ggctaagggc cggcggaaga ggccccaatg gg #gcggtgac   1560 cccagcctcg cccgacagag cccggggcgc aggcgggcgc cagggcgcta at #cccggcgc   1620 gggttccgct gacgcagcgc cccgcctggg agccgcgggc aggcgagact gg #cggagccc   1680 ccagacctcc cagtggggac ggggcagggc ctggcctggg aagagcacag ct #gcagatcc   1740 caggcctctg gcgcccccac tcaagactac caaagccagg acacctcaag tc #tccagccc   1800 caatacccca ccccaatccc gtattctttt tttttttttt ttagacaggg tc #ttgctccg   1860 ttgcccaggt tggagtgcag tggcccatca gggctcactg taacctccga ct #cctgggtt   1920 caagtgaccc tcccacctca gcctctcaag tagctgggac tacaggtgca cc #accacacc   1980 tggctaattt ttgtattttt tgtaaagagg ggggtctcac tgtgttgccc ag #gctggttt   2040 cgaactcctg ggctcaagcg gtccacctgc ctccgcctcc caaagtgctg gg #attgcagg   2100 catgagccac tgcacccagc cctgtattct tattcttcag atatttattt tt #cttttcac   2160 tgttttaaaa taaaaccaaa gtattgataa aaaaaaa       #                   #    2197 <210> SEQ ID NO 12 <211> LENGTH: 164 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 Met Trp Arg Cys Pro Leu Gly Leu Leu Leu Le #u Leu Pro Leu Ala Gly   1               5  #                 10  #                 15 His Leu Ala Leu Gly Ala Gln Gln Gly Arg Gl #y Arg Arg Glu Leu Ala              20      #             25      #             30 Pro Gly Leu His Leu Arg Gly Ile Arg Asp Al #a Gly Gly Arg Tyr Cys          35          #         40          #         45 Gln Glu Gln Asp Leu Cys Cys Arg Gly Arg Al #a Asp Asp Cys Ala Leu      50              #     55              #     60 Pro Tyr Leu Gly Ala Ile Cys Tyr Cys Asp Le #u Phe Cys Asn Arg Thr  65                  # 70                  # 75                  # 80 Val Ser Asp Cys Cys Pro Asp Phe Trp Asp Ph #e Cys Leu Gly Val Pro                  85  #                 90  #                 95 Pro Pro Phe Pro Pro Ile Gln Gly Cys Met Hi #s Gly Gly Arg Ile Tyr             100       #           105       #           110 Pro Val Leu Gly Thr Tyr Trp Asp Asn Cys As #n Arg Cys Thr Cys Gln         115           #       120           #       125 Glu Asn Arg Gln Trp His Gly Gly Ser Arg Hi #s Asp Gln Ser His Gln     130               #   135               #   140 Pro Gly Gln Leu Trp Leu Ala Gly Trp Glu Pr #o Gln Arg Leu Leu Gly 145                 1 #50                 1 #55                 1 #60 His Asp Pro Gly <210> SEQ ID NO 13 <211> LENGTH: 533 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (33) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (80) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (94) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (144) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (188) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 13 aggctccttg gccctttttc cacagcaagc ttntgcnatc ccgattcgtt gt #ctcaaatc     60 caattctctt gggacacatn acgcctgtcc tttngcccca gaacctgctg tc #ttgtacac    120 ccaccagcag cagggctgcc gcgntgggcg tctcgatggt gcctggtggt tc #ctgcgtcg    180 ccgagggntg gtgtctgacc actgctaccc cttctcgggc cgtgaacgag ac #gaggctgg    240 ccctgcgccc ccctgtatga tgcacagccg agccatgggt cggggcaagc gc #caggccac    300 tgcccactgc cccaacagct atgttaataa caatgacatc taccaggtca ct #cctgtcta    360 ccgcctcggc tccaacgaca aggagatcat gaaggagctg atggagaatg gc #cctgtcca    420 agccctcatg gaggtgcatg aggacttctt cctatacaag ggaggcatct ac #agccacac    480 gccagtgagc cttgggaggc cagagagata ccgccggcat gggacccact ca #g           533 <210> SEQ ID NO 14 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 14 ttcgaggcct ctgagaagtg gccc           #                   #                24 <210> SEQ ID NO 15 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 15 ggcggtatct ctctggcctc cc            #                   #                 22 <210> SEQ ID NO 16 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 16 ttctccacag cagctgtggc atccgatcgt gtctcaatcc attctctggg   #              50 <210> SEQ ID NO 17 <211> LENGTH: 960 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 gctgcttgcc ctgttgatgg caggcttggc cctgcagcca ggcactgccc tg #ctgtgcta     60 ctcctgcaaa gcccaggtga gcaacgagga ctgcctgcag gtggagaact gc #acccagct    120 gggggagcag tgctggaccg cgcgcatccg cgcagttggc ctcctgaccg tc #atcagcaa    180 aggctgcagc ttgaactgcg tggatgactc acaggactac tacgtgggca ag #aagaacat    240 cacgtgctgt gacaccgact tgtgcaacgc cagcggggcc catgccctgc ag #ccggctgc    300 cgccatcctt gcgctgctcc ctgcactcgg cctgctgctc tggggacccg gc #cagctata    360 ggctctgggg ggccccgctg cagcccacac tgggtgtggt gccccaggcc tc #tgtgccac    420 tcctcacaga cctggcccag tgggagcctg tcctggttcc tgaggcacat cc #taacgcaa    480 gtctgaccat gtatgtctgc acccctgtcc cccaccctga ccctcccatg gc #cctctcca    540 ggactcccac ccggcagatc agctctagtg acacagatcc gcctgcagat gg #cccctcca    600 accctctctg ctgctgtttc catggcccag cattctccac ccttaaccct gt #gctcaggc    660 acctcttccc ccaggaagcc ttccctgccc accccatcta tgacttgagc ca #ggtctggt    720 ccgtggtgtc ccccgcaccc agcaggggac aggcactcag gagggcccag ta #aaggctga    780 gatgaagtgg actgagtaga actggaggac aagagtcgac gtgagttcct gg #gagtctcc    840 agagatgggg cctggaggcc tggaggaagg ggccaggcct cacattcgtg gg #gctccctg    900 aatggcagcc tgagcacagc gtaggccctt aataaacacc tgttggataa gc #caaaaaaa    960 <210> SEQ ID NO 18 <211> LENGTH: 189 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met Thr His Arg Thr Thr Thr Trp Ala Arg Ar #g Thr Ser Arg Ala Val   1               5  #                 10  #                 15 Thr Pro Thr Cys Ala Thr Pro Ala Gly Pro Me #t Pro Cys Ser Arg Leu              20      #             25      #             30 Pro Pro Ser Leu Arg Cys Ser Leu His Ser Al #a Cys Cys Ser Gly Asp          35          #         40          #         45 Pro Ala Ser Tyr Arg Leu Trp Gly Ala Pro Le #u Gln Pro Thr Leu Gly      50              #     55              #     60 Val Val Pro Gln Ala Ser Val Pro Leu Leu Th #r Asp Leu Ala Gln Trp  65                  # 70                  # 75                  # 80 Glu Pro Val Leu Val Pro Glu Ala His Pro As #n Ala Ser Leu Thr Met                  85  #                 90  #                 95 Tyr Val Cys Thr Pro Val Pro His Pro Asp Pr #o Pro Met Ala Leu Ser             100       #           105       #           110 Arg Thr Pro Thr Arg Gln Ile Ser Ser Ser As #p Thr Asp Pro Pro Ala         115           #       120           #       125 Asp Gly Pro Ser Asn Pro Leu Cys Cys Cys Ph #e His Gly Pro Ala Phe     130               #   135               #   140 Ser Thr Leu Asn Pro Val Leu Arg His Leu Ph #e Pro Gln Glu Ala Phe 145                 1 #50                 1 #55                 1 #60 Pro Ala His Pro Ile Tyr Asp Leu Ser Gln Va #l Trp Ser Val Val Ser                 165   #               170   #               175 Pro Ala Pro Ser Arg Gly Gln Ala Leu Arg Ar #g Ala Gln             180       #           185 <210> SEQ ID NO 19 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 19 tgctgtgcta ctcctgcaaa gccc           #                   #                24 <210> SEQ ID NO 20 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 20 tgcacaagtc ggtgtcacag cacg           #                   #                24 <210> SEQ ID NO 21 <211> LENGTH: 44 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 21 agcaacgagg actgcctgca ggtggagaac tgcacccagc tggg    #                   # 44 <210> SEQ ID NO 22 <211> LENGTH: 1200 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 cccacgcgtc cgaacctctc cagcgatggg agccgcccgc ctgctgccca ac #ctcactct     60 gtgcttacag ctgctgattc tctgctgtca aactcagtac gtgagggacc ag #ggcgccat    120 gaccgaccag ctgagcaggc ggcagatccg cgagtaccaa ctctacagca gg #accagtgg    180 caagcacgtg caggtcaccg ggcgtcgcat ctccgccacc gccgaggacg gc #aacaagtt    240 tgccaagctc atagtggaga cggacacgtt tggcagccgg gttcgcatca aa #ggggctga    300 gagtgagaag tacatctgta tgaacaagag gggcaagctc atcgggaagc cc #agcgggaa    360 gagcaaagac tgcgtgttca cggagatcgt gctggagaac aactatacgg cc #ttccagaa    420 cgcccggcac gagggctggt tcatggcctt cacgcggcag gggcggcccc gc #caggcttc    480 ccgcagccgc cagaaccagc gcgaggccca cttcatcaag cgcctctacc aa #ggccagct    540 gcccttcccc aaccacgccg agaagcagaa gcagttcgag tttgtgggct cc #gcccccac    600 ccgccggacc aagcgcacac ggcggcccca gcccctcacg tagtctggga gg #cagggggc    660 agcagcccct gggccgcctc cccacccctt tcccttctta atccaaggac tg #ggctgggg    720 tggcgggagg ggagccagat ccccgaggga ggaccctgag ggccgcgaag ca #tccgagcc    780 cccagctggg aaggggcagg ccggtgcccc aggggcggct ggcacagtgc cc #ccttcccg    840 gacgggtggc aggccctgga gaggaactga gtgtcaccct gatctcaggc ca #ccagcctc    900 tgccggcctc ccagccgggc tcctgaagcc cgctgaaagg tcagcgactg aa #ggccttgc    960 agacaaccgt ctggaggtgg ctgtcctcaa aatctgcttc tcggatctcc ct #cagtctgc   1020 ccccagcccc caaactcctc ctggctagac tgtaggaagg gacttttgtt tg #tttgtttg   1080 tttcaggaaa aaagaaaggg agagagagga aaatagaggg ttgtccactc ct #cacattcc   1140 acgacccagg cctgcacccc acccccaact cccagccccg gaataaaacc at #tttcctgc   1200 <210> SEQ ID NO 23 <211> LENGTH: 205 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Met Gly Ala Ala Arg Leu Leu Pro Asn Leu Th #r Leu Cys Leu Gln Leu   1               5  #                 10  #                 15 Leu Ile Leu Cys Cys Gln Thr Gln Tyr Val Ar #g Asp Gln Gly Ala Met              20      #             25      #             30 Thr Asp Gln Leu Ser Arg Arg Gln Ile Arg Gl #u Tyr Gln Leu Tyr Ser          35          #         40          #         45 Arg Thr Ser Gly Lys His Val Gln Val Thr Gl #y Arg Arg Ile Ser Ala      50              #     55              #     60 Thr Ala Glu Asp Gly Asn Lys Phe Ala Lys Le #u Ile Val Glu Thr Asp  65                  # 70                  # 75                  # 80 Thr Phe Gly Ser Arg Val Arg Ile Lys Gly Al #a Glu Ser Glu Lys Tyr                  85  #                 90  #                 95 Ile Cys Met Asn Lys Arg Gly Lys Leu Ile Gl #y Lys Pro Ser Gly Lys             100       #           105       #           110 Ser Lys Asp Cys Val Phe Thr Glu Ile Val Le #u Glu Asn Asn Tyr Thr         115           #       120           #       125 Ala Phe Gln Asn Ala Arg His Glu Gly Trp Ph #e Met Ala Phe Thr Arg     130               #   135               #   140 Gln Gly Arg Pro Arg Gln Ala Ser Arg Ser Ar #g Gln Asn Gln Arg Glu 145                 1 #50                 1 #55                 1 #60 Ala His Phe Ile Lys Arg Leu Tyr Gln Gly Gl #n Leu Pro Phe Pro Asn                 165   #               170   #               175 His Ala Glu Lys Gln Lys Gln Phe Glu Phe Va #l Gly Ser Ala Pro Thr             180       #           185       #           190 Arg Arg Thr Lys Arg Thr Arg Arg Pro Gln Pr #o Leu Thr         195           #       200           #       205 <210> SEQ ID NO 24 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 24 cagtacgtga gggaccaggg cgccatga          #                   #             28 <210> SEQ ID NO 25 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 25 ccggtgacct gcacgtgctt gcca           #                   #                24 <210> SEQ ID NO 26 <211> LENGTH: 41 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <221> NAME/KEY: modified_base <222> LOCATION: (21) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 26 gcggatctgc cgcctgctca nctggtcggt catggcgccc t     #                   #   41 <210> SEQ ID NO 27 <211> LENGTH: 2479 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 acttgccatc acctgttgcc agtgtggaaa aattctccct gttgaatttt tt #gcacatgg     60 aggacagcag caaagagggc aacacaggct gataagacca gagacagcag gg #agattatt    120 ttaccatacg ccctcaggac gttccctcta gctggagttc tggacttcaa ca #gaacccca    180 tccagtcatt ttgattttgc tgtttatttt ttttttcttt ttctttttcc ca #ccacattg    240 tattttattt ccgtacttca gaaatgggcc tacagaccac aaagtggccc ag #ccatgggg    300 cttttttcct gaagtcttgg cttatcattt ccctggggct ctactcacag gt #gtccaaac    360 tcctggcctg ccctagtgtg tgccgctgcg acaggaactt tgtctactgt aa #tgagcgaa    420 gcttgacctc agtgcctctt gggatcccgg agggcgtaac cgtactctac ct #ccacaaca    480 accaaattaa taatgctgga tttcctgcag aactgcacaa tgtacagtcg gt #gcacacgg    540 tctacctgta tggcaaccaa ctggacgaat tccccatgaa ccttcccaag aa #tgtcagag    600 ttctccattt gcaggaaaac aatattcaga ccatttcacg ggctgctctt gc #ccagctct    660 tgaagcttga agagctgcac ctggatgaca actccatatc cacagtgggg gt #ggaagacg    720 gggccttccg ggaggctatt agcctcaaat tgttgttttt gtctaagaat ca #cctgagca    780 gtgtgcctgt tgggcttcct gtggacttgc aagagctgag agtggatgaa aa #tcgaattg    840 ctgtcatatc cgacatggcc ttccagaatc tcacgagctt ggagcgtctt at #tgtggacg    900 ggaacctcct gaccaacaag ggtatcgccg agggcacctt cagccatctc ac #caagctca    960 aggaattttc aattgtacgt aattcgctgt cccaccctcc tcccgatctc cc #aggtacgc   1020 atctgatcag gctctatttg caggacaacc agataaacca cattcctttg ac #agccttct   1080 caaatctgcg taagctggaa cggctggata tatccaacaa ccaactgcgg at #gctgactc   1140 aaggggtttt tgataatctc tccaacctga agcagctcac tgctcggaat aa #cccttggt   1200 tttgtgactg cagtattaaa tgggtcacag aatggctcaa atatatccct tc #atctctca   1260 acgtgcgggg tttcatgtgc caaggtcctg aacaagtccg ggggatggcc gt #cagggaat   1320 taaatatgaa tcttttgtcc tgtcccacca cgacccccgg cctgcctctc tt #caccccag   1380 ccccaagtac agcttctccg accactcagc ctcccaccct ctctattcca aa #ccctagca   1440 gaagctacac gcctccaact cctaccacat cgaaacttcc cacgattcct ga #ctgggatg   1500 gcagagaaag agtgacccca cctatttctg aacggatcca gctctctatc ca #ttttgtga   1560 atgatacttc cattcaagtc agctggctct ctctcttcac cgtgatggca ta #caaactca   1620 catgggtgaa aatgggccac agtttagtag ggggcatcgt tcaggagcgc at #agtcagcg   1680 gtgagaagca acacctgagc ctggttaact tagagccccg atccacctat cg #gatttgtt   1740 tagtgccact ggatgctttt aactaccgcg cggtagaaga caccatttgt tc #agaggcca   1800 ccacccatgc ctcctatctg aacaacggca gcaacacagc gtccagccat ga #gcagacga   1860 cgtcccacag catgggctcc ccctttctgc tggcgggctt gatcgggggc gc #ggtgatat   1920 ttgtgctggt ggtcttgctc agcgtctttt gctggcatat gcacaaaaag gg #gcgctaca   1980 cctcccagaa gtggaaatac aaccggggcc ggcggaaaga tgattattgc ga #ggcaggca   2040 ccaagaagga caactccatc ctggagatga cagaaaccag ttttcagatc gt #ctccttaa   2100 ataacgatca actccttaaa ggagatttca gactgcagcc catttacacc cc #aaatgggg   2160 gcattaatta cacagactgc catatcccca acaacatgcg atactgcaac ag #cagcgtgc   2220 cagacctgga gcactgccat acgtgacagc cagaggccca gcgttatcaa gg #cggacaat   2280 tagactcttg agaacacact cgtgtgtgca cataaagaca cgcagattac at #ttgataaa   2340 tgttacacag atgcatttgt gcatttgaat actctgtaat ttatacggtg ta #ctatataa   2400 tgggatttaa aaaaagtgct atcttttcta tttcaagtta attacaaaca gt #tttgtaac   2460 tctttgcttt ttaaatctt              #                   #                 247 #9 <210> SEQ ID NO 28 <211> LENGTH: 660 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Met Gly Leu Gln Thr Thr Lys Trp Pro Ser Hi #s Gly Ala Phe Phe Leu   1               5  #                 10  #                 15 Lys Ser Trp Leu Ile Ile Ser Leu Gly Leu Ty #r Ser Gln Val Ser Lys              20      #             25      #             30 Leu Leu Ala Cys Pro Ser Val Cys Arg Cys As #p Arg Asn Phe Val Tyr          35          #         40          #         45 Cys Asn Glu Arg Ser Leu Thr Ser Val Pro Le #u Gly Ile Pro Glu Gly      50              #     55              #     60 Val Thr Val Leu Tyr Leu His Asn Asn Gln Il #e Asn Asn Ala Gly Phe  65                  # 70                  # 75                  # 80 Pro Ala Glu Leu His Asn Val Gln Ser Val Hi #s Thr Val Tyr Leu Tyr                  85  #                 90  #                 95 Gly Asn Gln Leu Asp Glu Phe Pro Met Asn Le #u Pro Lys Asn Val Arg             100       #           105       #           110 Val Leu His Leu Gln Glu Asn Asn Ile Gln Th #r Ile Ser Arg Ala Ala         115           #       120           #       125 Leu Ala Gln Leu Leu Lys Leu Glu Glu Leu Hi #s Leu Asp Asp Asn Ser     130               #   135               #   140 Ile Ser Thr Val Gly Val Glu Asp Gly Ala Ph #e Arg Glu Ala Ile Ser 145                 1 #50                 1 #55                 1 #60 Leu Lys Leu Leu Phe Leu Ser Lys Asn His Le #u Ser Ser Val Pro Val                 165   #               170   #               175 Gly Leu Pro Val Asp Leu Gln Glu Leu Arg Va #l Asp Glu Asn Arg Ile             180       #           185       #           190 Ala Val Ile Ser Asp Met Ala Phe Gln Asn Le #u Thr Ser Leu Glu Arg         195           #       200           #       205 Leu Ile Val Asp Gly Asn Leu Leu Thr Asn Ly #s Gly Ile Ala Glu Gly     210               #   215               #   220 Thr Phe Ser His Leu Thr Lys Leu Lys Glu Ph #e Ser Ile Val Arg Asn 225                 2 #30                 2 #35                 2 #40 Ser Leu Ser His Pro Pro Pro Asp Leu Pro Gl #y Thr His Leu Ile Arg                 245   #               250   #               255 Leu Tyr Leu Gln Asp Asn Gln Ile Asn His Il #e Pro Leu Thr Ala Phe             260       #           265       #           270 Ser Asn Leu Arg Lys Leu Glu Arg Leu Asp Il #e Ser Asn Asn Gln Leu         275           #       280           #       285 Arg Met Leu Thr Gln Gly Val Phe Asp Asn Le #u Ser Asn Leu Lys Gln     290               #   295               #   300 Leu Thr Ala Arg Asn Asn Pro Trp Phe Cys As #p Cys Ser Ile Lys Trp 305                 3 #10                 3 #15                 3 #20 Val Thr Glu Trp Leu Lys Tyr Ile Pro Ser Se #r Leu Asn Val Arg Gly                 325   #               330   #               335 Phe Met Cys Gln Gly Pro Glu Gln Val Arg Gl #y Met Ala Val Arg Glu             340       #           345       #           350 Leu Asn Met Asn Leu Leu Ser Cys Pro Thr Th #r Thr Pro Gly Leu Pro         355           #       360           #       365 Leu Phe Thr Pro Ala Pro Ser Thr Ala Ser Pr #o Thr Thr Gln Pro Pro     370               #   375               #   380 Thr Leu Ser Ile Pro Asn Pro Ser Arg Ser Ty #r Thr Pro Pro Thr Pro 385                 3 #90                 3 #95                 4 #00 Thr Thr Ser Lys Leu Pro Thr Ile Pro Asp Tr #p Asp Gly Arg Glu Arg                 405   #               410   #               415 Val Thr Pro Pro Ile Ser Glu Arg Ile Gln Le #u Ser Ile His Phe Val             420       #           425       #           430 Asn Asp Thr Ser Ile Gln Val Ser Trp Leu Se #r Leu Phe Thr Val Met         435           #       440           #       445 Ala Tyr Lys Leu Thr Trp Val Lys Met Gly Hi #s Ser Leu Val Gly Gly     450               #   455               #   460 Ile Val Gln Glu Arg Ile Val Ser Gly Glu Ly #s Gln His Leu Ser Leu 465                 4 #70                 4 #75                 4 #80 Val Asn Leu Glu Pro Arg Ser Thr Tyr Arg Il #e Cys Leu Val Pro Leu                 485   #               490   #               495 Asp Ala Phe Asn Tyr Arg Ala Val Glu Asp Th #r Ile Cys Ser Glu Ala             500       #           505       #           510 Thr Thr His Ala Ser Tyr Leu Asn Asn Gly Se #r Asn Thr Ala Ser Ser         515           #       520           #       525 His Glu Gln Thr Thr Ser His Ser Met Gly Se #r Pro Phe Leu Leu Ala     530               #   535               #   540 Gly Leu Ile Gly Gly Ala Val Ile Phe Val Le #u Val Val Leu Leu Ser 545                 5 #50                 5 #55                 5 #60 Val Phe Cys Trp His Met His Lys Lys Gly Ar #g Tyr Thr Ser Gln Lys                 565   #               570   #               575 Trp Lys Tyr Asn Arg Gly Arg Arg Lys Asp As #p Tyr Cys Glu Ala Gly             580       #           585       #           590 Thr Lys Lys Asp Asn Ser Ile Leu Glu Met Th #r Glu Thr Ser Phe Gln         595           #       600           #       605 Ile Val Ser Leu Asn Asn Asp Gln Leu Leu Ly #s Gly Asp Phe Arg Leu     610               #   615               #   620 Gln Pro Ile Tyr Thr Pro Asn Gly Gly Ile As #n Tyr Thr Asp Cys His 625                 6 #30                 6 #35                 6 #40 Ile Pro Asn Asn Met Arg Tyr Cys Asn Ser Se #r Val Pro Asp Leu Glu                 645   #               650   #               655 His Cys His Thr             660 <210> SEQ ID NO 29 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 29 cggtctacct gtatggcaac c            #                   #                   #21 <210> SEQ ID NO 30 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 30 gcaggacaac cagataaacc ac            #                   #                 22 <210> SEQ ID NO 31 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 31 acgcagattt gagaaggctg tc            #                   #                 22 <210> SEQ ID NO 32 <211> LENGTH: 46 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 32 ttcacgggct gctcttgccc agctcttgaa gcttgaagag ctgcac    #                 46 <210> SEQ ID NO 33 <211> LENGTH: 3449 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 acttggagca agcggcggcg gcggagacag aggcagaggc agaagctggg gc #tccgtcct     60 cgcctcccac gagcgatccc cgaggagagc cgcggccctc ggcgaggcga ag #aggccgac    120 gaggaagacc cgggtggctg cgcccctgcc tcgcttccca ggcgccggcg gc #tgcagcct    180 tgcccctctt gctcgccttg aaaatggaaa agatgctcgc aggctgcttt ct #gctgatcc    240 tcggacagat cgtcctcctc cctgccgagg ccagggagcg gtcacgtggg ag #gtccatct    300 ctaggggcag acacgctcgg acccacccgc agacggccct tctggagagt tc #ctgtgaga    360 acaagcgggc agacctggtt ttcatcattg acagctctcg cagtgtcaac ac #ccatgact    420 atgcaaaggt caaggagttc atcgtggaca tcttgcaatt cttggacatt gg #tcctgatg    480 tcacccgagt gggcctgctc caatatggca gcactgtcaa gaatgagttc tc #cctcaaga    540 ccttcaagag gaagtccgag gtggagcgtg ctgtcaagag gatgcggcat ct #gtccacgg    600 gcaccatgac tgggctggcc atccagtatg ccctgaacat cgcattctca ga #agcagagg    660 gggcccggcc cctgagggag aatgtgccac gggtcataat gatcgtgaca ga #tgggagac    720 ctcaggactc cgtggccgag gtggctgcta aggcacggga cacgggcatc ct #aatctttg    780 ccattggtgt gggccaggta gacttcaaca ccttgaagtc cattgggagt ga #gccccatg    840 aggaccatgt cttccttgtg gccaatttca gccagattga gacgctgacc tc #cgtgttcc    900 agaagaagtt gtgcacggcc cacatgtgca gcaccctgga gcataactgt gc #ccacttct    960 gcatcaacat ccctggctca tacgtctgca ggtgcaaaca aggctacatt ct #caactcgg   1020 atcagacgac ttgcagaatc caggatctgt gtgccatgga ggaccacaac tg #tgagcagc   1080 tctgtgtgaa tgtgccgggc tccttcgtct gccagtgcta cagtggctac gc #cctggctg   1140 aggatgggaa gaggtgtgtg gctgtggact actgtgcctc agaaaaccac gg #atgtgaac   1200 atgagtgtgt aaatgctgat ggctcctacc tttgccagtg ccatgaagga tt #tgctctta   1260 acccagatga aaaaacgtgc acaaggatca actactgtgc actgaacaaa cc #gggctgtg   1320 agcatgagtg cgtcaacatg gaggagagct actactgccg ctgccaccgt gg #ctacactc   1380 tggaccccaa tggcaaaacc tgcagccgag tggaccactg tgcacagcag ga #ccatggct   1440 gtgagcagct gtgtctgaac acggaggatt ccttcgtctg ccagtgctca ga #aggcttcc   1500 tcatcaacga ggacctcaag acctgctccc gggtggatta ctgcctgctg ag #tgaccatg   1560 gttgtgaata ctcctgtgtc aacatggaca gatcctttgc ctgtcagtgt cc #tgagggac   1620 acgtgctccg cagcgatggg aagacgtgtg caaaattgga ctcttgtgct ct #gggggacc   1680 acggttgtga acattcgtgt gtaagcagtg aagattcgtt tgtgtgccag tg #ctttgaag   1740 gttatatact ccgtgaagat ggaaaaacct gcagaaggaa agatgtctgc ca #agctatag   1800 accatggctg tgaacacatt tgtgtgaaca gtgacgactc atacacgtgc ga #gtgcttgg   1860 agggattccg gctcgctgag gatgggaaac gctgccgaag gaaggatgtc tg #caaatcaa   1920 cccaccatgg ctgcgaacac atttgtgtta ataatgggaa ttcctacatc tg #caaatgct   1980 cagagggatt tgttctagct gaggacggaa gacggtgcaa gaaatgcact ga #aggcccaa   2040 ttgacctggt ctttgtgatc gatggatcca agagtcttgg agaagagaat tt #tgaggtcg   2100 tgaagcagtt tgtcactgga attatagatt ccttgacaat ttcccccaaa gc #cgctcgag   2160 tggggctgct ccagtattcc acacaggtcc acacagagtt cactctgaga aa #cttcaact   2220 cagccaaaga catgaaaaaa gccgtggccc acatgaaata catgggaaag gg #ctctatga   2280 ctgggctggc cctgaaacac atgtttgaga gaagttttac ccaaggagaa gg #ggccaggc   2340 ccctttccac aagggtgccc agagcagcca ttgtgttcac cgacggacgg gc #tcaggatg   2400 acgtctccga gtgggccagt aaagccaagg ccaatggtat cactatgtat gc #tgttgggg   2460 taggaaaagc cattgaggag gaactacaag agattgcctc tgagcccaca aa #caagcatc   2520 tcttctatgc cgaagacttc agcacaatgg atgagataag tgaaaaactc aa #gaaaggca   2580 tctgtgaagc tctagaagac tccgatggaa gacaggactc tccagcaggg ga #actgccaa   2640 aaacggtcca acagccaaca gaatctgagc cagtcaccat aaatatccaa ga #cctacttt   2700 cctgttctaa ttttgcagtg caacacagat atctgtttga agaagacaat ct #tttacggt   2760 ctacacaaaa gctttcccat tcaacaaaac cttcaggaag ccctttggaa ga #aaaacacg   2820 atcaatgcaa atgtgaaaac cttataatgt tccagaacct tgcaaacgaa ga #agtaagaa   2880 aattaacaca gcgcttagaa gaaatgacac agagaatgga agccctggaa aa #tcgcctga   2940 gatacagatg aagattagaa atcgcgacac atttgtagtc attgtatcac gg #attacaat   3000 gaacgcagtg cagagcccca aagctcaggc tattgttaaa tcaataatgt tg #tgaagtaa   3060 aacaatcagt actgagaaac ctggtttgcc acagaacaaa gacaagaagt at #acactaac   3120 ttgtataaat ttatctagga aaaaaatcct tcagaattct aagatgaatt ta #ccaggtga   3180 gaatgaataa gctatgcaag gtattttgta atatactgtg gacacaactt gc #ttctgcct   3240 catcctgcct tagtgtgcaa tctcatttga ctatacgata aagtttgcac ag #tcttactt   3300 ctgtagaaca ctggccatag gaaatgctgt ttttttgtac tggactttac ct #tgatatat   3360 gtatatggat gtatgcataa aatcatagga catatgtact tgtggaacaa gt #tggatttt   3420 ttatacaata ttaaaattca ccacttcag          #                   #          3449 <210> SEQ ID NO 34 <211> LENGTH: 915 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Met Glu Lys Met Leu Ala Gly Cys Phe Leu Le #u Ile Leu Gly Gln Ile   1               5  #                 10  #                 15 Val Leu Leu Pro Ala Glu Ala Arg Glu Arg Se #r Arg Gly Arg Ser Ile              20      #             25      #             30 Ser Arg Gly Arg His Ala Arg Thr His Pro Gl #n Thr Ala Leu Leu Glu          35          #         40          #         45 Ser Ser Cys Glu Asn Lys Arg Ala Asp Leu Va #l Phe Ile Ile Asp Ser      50              #     55              #     60 Ser Arg Ser Val Asn Thr His Asp Tyr Ala Ly #s Val Lys Glu Phe Ile  65                  # 70                  # 75                  # 80 Val Asp Ile Leu Gln Phe Leu Asp Ile Gly Pr #o Asp Val Thr Arg Val                  85  #                 90  #                 95 Gly Leu Leu Gln Tyr Gly Ser Thr Val Lys As #n Glu Phe Ser Leu Lys             100       #           105       #           110 Thr Phe Lys Arg Lys Ser Glu Val Glu Arg Al #a Val Lys Arg Met Arg         115           #       120           #       125 His Leu Ser Thr Gly Thr Met Thr Gly Leu Al #a Ile Gln Tyr Ala Leu     130               #   135               #   140 Asn Ile Ala Phe Ser Glu Ala Glu Gly Ala Ar #g Pro Leu Arg Glu Asn 145                 1 #50                 1 #55                 1 #60 Val Pro Arg Val Ile Met Ile Val Thr Asp Gl #y Arg Pro Gln Asp Ser                 165   #               170   #               175 Val Ala Glu Val Ala Ala Lys Ala Arg Asp Th #r Gly Ile Leu Ile Phe             180       #           185       #           190 Ala Ile Gly Val Gly Gln Val Asp Phe Asn Th #r Leu Lys Ser Ile Gly         195           #       200           #       205 Ser Glu Pro His Glu Asp His Val Phe Leu Va #l Ala Asn Phe Ser Gln     210               #   215               #   220 Ile Glu Thr Leu Thr Ser Val Phe Gln Lys Ly #s Leu Cys Thr Ala His 225                 2 #30                 2 #35                 2 #40 Met Cys Ser Thr Leu Glu His Asn Cys Ala Hi #s Phe Cys Ile Asn Ile                 245   #               250   #               255 Pro Gly Ser Tyr Val Cys Arg Cys Lys Gln Gl #y Tyr Ile Leu Asn Ser             260       #           265       #           270 Asp Gln Thr Thr Cys Arg Ile Gln Asp Leu Cy #s Ala Met Glu Asp His         275           #       280           #       285 Asn Cys Glu Gln Leu Cys Val Asn Val Pro Gl #y Ser Phe Val Cys Gln     290               #   295               #   300 Cys Tyr Ser Gly Tyr Ala Leu Ala Glu Asp Gl #y Lys Arg Cys Val Ala 305                 3 #10                 3 #15                 3 #20 Val Asp Tyr Cys Ala Ser Glu Asn His Gly Cy #s Glu His Glu Cys Val                 325   #               330   #               335 Asn Ala Asp Gly Ser Tyr Leu Cys Gln Cys Hi #s Glu Gly Phe Ala Leu             340       #           345       #           350 Asn Pro Asp Glu Lys Thr Cys Thr Arg Ile As #n Tyr Cys Ala Leu Asn         355           #       360           #       365 Lys Pro Gly Cys Glu His Glu Cys Val Asn Me #t Glu Glu Ser Tyr Tyr     370               #   375               #   380 Cys Arg Cys His Arg Gly Tyr Thr Leu Asp Pr #o Asn Gly Lys Thr Cys 385                 3 #90                 3 #95                 4 #00 Ser Arg Val Asp His Cys Ala Gln Gln Asp Hi #s Gly Cys Glu Gln Leu                 405   #               410   #               415 Cys Leu Asn Thr Glu Asp Ser Phe Val Cys Gl #n Cys Ser Glu Gly Phe             420       #           425       #           430 Leu Ile Asn Glu Asp Leu Lys Thr Cys Ser Ar #g Val Asp Tyr Cys Leu         435           #       440           #       445 Leu Ser Asp His Gly Cys Glu Tyr Ser Cys Va #l Asn Met Asp Arg Ser     450               #   455               #   460 Phe Ala Cys Gln Cys Pro Glu Gly His Val Le #u Arg Ser Asp Gly Lys 465                 4 #70                 4 #75                 4 #80 Thr Cys Ala Lys Leu Asp Ser Cys Ala Leu Gl #y Asp His Gly Cys Glu                 485   #               490   #               495 His Ser Cys Val Ser Ser Glu Asp Ser Phe Va #l Cys Gln Cys Phe Glu             500       #           505       #           510 Gly Tyr Ile Leu Arg Glu Asp Gly Lys Thr Cy #s Arg Arg Lys Asp Val         515           #       520           #       525 Cys Gln Ala Ile Asp His Gly Cys Glu His Il #e Cys Val Asn Ser Asp     530               #   535               #   540 Asp Ser Tyr Thr Cys Glu Cys Leu Glu Gly Ph #e Arg Leu Ala Glu Asp 545                 5 #50                 5 #55                 5 #60 Gly Lys Arg Cys Arg Arg Lys Asp Val Cys Ly #s Ser Thr His His Gly                 565   #               570   #               575 Cys Glu His Ile Cys Val Asn Asn Gly Asn Se #r Tyr Ile Cys Lys Cys             580       #           585       #           590 Ser Glu Gly Phe Val Leu Ala Glu Asp Gly Ar #g Arg Cys Lys Lys Cys         595           #       600           #       605 Thr Glu Gly Pro Ile Asp Leu Val Phe Val Il #e Asp Gly Ser Lys Ser     610               #   615               #   620 Leu Gly Glu Glu Asn Phe Glu Val Val Lys Gl #n Phe Val Thr Gly Ile 625                 6 #30                 6 #35                 6 #40 Ile Asp Ser Leu Thr Ile Ser Pro Lys Ala Al #a Arg Val Gly Leu Leu                 645   #               650   #               655 Gln Tyr Ser Thr Gln Val His Thr Glu Phe Th #r Leu Arg Asn Phe Asn             660       #           665       #           670 Ser Ala Lys Asp Met Lys Lys Ala Val Ala Hi #s Met Lys Tyr Met Gly         675           #       680           #       685 Lys Gly Ser Met Thr Gly Leu Ala Leu Lys Hi #s Met Phe Glu Arg Ser     690               #   695               #   700 Phe Thr Gln Gly Glu Gly Ala Arg Pro Leu Se #r Thr Arg Val Pro Arg 705                 7 #10                 7 #15                 7 #20 Ala Ala Ile Val Phe Thr Asp Gly Arg Ala Gl #n Asp Asp Val Ser Glu                 725   #               730   #               735 Trp Ala Ser Lys Ala Lys Ala Asn Gly Ile Th #r Met Tyr Ala Val Gly             740       #           745       #           750 Val Gly Lys Ala Ile Glu Glu Glu Leu Gln Gl #u Ile Ala Ser Glu Pro         755           #       760           #       765 Thr Asn Lys His Leu Phe Tyr Ala Glu Asp Ph #e Ser Thr Met Asp Glu     770               #   775               #   780 Ile Ser Glu Lys Leu Lys Lys Gly Ile Cys Gl #u Ala Leu Glu Asp Ser 785                 7 #90                 7 #95                 8 #00 Asp Gly Arg Gln Asp Ser Pro Ala Gly Glu Le #u Pro Lys Thr Val Gln                 805   #               810   #               815 Gln Pro Thr Glu Ser Glu Pro Val Thr Ile As #n Ile Gln Asp Leu Leu             820       #           825       #           830 Ser Cys Ser Asn Phe Ala Val Gln His Arg Ty #r Leu Phe Glu Glu Asp         835           #       840           #       845 Asn Leu Leu Arg Ser Thr Gln Lys Leu Ser Hi #s Ser Thr Lys Pro Ser     850               #   855               #   860 Gly Ser Pro Leu Glu Glu Lys His Asp Gln Cy #s Lys Cys Glu Asn Leu 865                 8 #70                 8 #75                 8 #80 Ile Met Phe Gln Asn Leu Ala Asn Glu Glu Va #l Arg Lys Leu Thr Gln                 885   #               890   #               895 Arg Leu Glu Glu Met Thr Gln Arg Met Glu Al #a Leu Glu Asn Arg Leu             900       #           905       #           910 Arg Tyr Arg         915 <210> SEQ ID NO 35 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 35 gtgaccctgg ttgtgaatac tcc            #                   #                23 <210> SEQ ID NO 36 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 36 acagccatgg tctatagctt gg            #                   #                 22 <210> SEQ ID NO 37 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 37 gcctgtcagt gtcctgaggg acacgtgctc cgcagcgatg ggaag    #                   #45 <210> SEQ ID NO 38 <211> LENGTH: 1813 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 ggagccgccc tgggtgtcag cggctcggct cccgcgcacg ctccggccgt cg #cgcagcct     60 cggcacctgc aggtccgtgc gtcccgcggc tggcgcccct gactccgtcc cg #gccaggga    120 gggccatgat ttccctcccg gggcccctgg tgaccaactt gctgcggttt tt #gttcctgg    180 ggctgagtgc cctcgcgccc ccctcgcggg cccagctgca actgcacttg cc #cgccaacc    240 ggttgcaggc ggtggaggga ggggaagtgg tgcttccagc gtggtacacc tt #gcacgggg    300 aggtgtcttc atcccagcca tgggaggtgc cctttgtgat gtggttcttc aa #acagaaag    360 aaaaggagga tcaggtgttg tcctacatca atggggtcac aacaagcaaa cc #tggagtat    420 ccttggtcta ctccatgccc tcccggaacc tgtccctgcg gctggagggt ct #ccaggaga    480 aagactctgg cccctacagc tgctccgtga atgtgcaaga caaacaaggc aa #atctaggg    540 gccacagcat caaaacctta gaactcaatg tactggttcc tccagctcct cc #atcctgcc    600 gtctccaggg tgtgccccat gtgggggcaa acgtgaccct gagctgccag tc #tccaagga    660 gtaagcccgc tgtccaatac cagtgggatc ggcagcttcc atccttccag ac #tttctttg    720 caccagcatt agatgtcatc cgtgggtctt taagcctcac caacctttcg tc #ttccatgg    780 ctggagtcta tgtctgcaag gcccacaatg aggtgggcac tgcccaatgt aa #tgtgacgc    840 tggaagtgag cacagggcct ggagctgcag tggttgctgg agctgttgtg gg #taccctgg    900 ttggactggg gttgctggct gggctggtcc tcttgtacca ccgccggggc aa #ggccctgg    960 aggagccagc caatgatatc aaggaggatg ccattgctcc ccggaccctg cc #ctggccca   1020 agagctcaga cacaatctcc aagaatggga ccctttcctc tgtcacctcc gc #acgagccc   1080 tccggccacc ccatggccct cccaggcctg gtgcattgac ccccacgccc ag #tctctcca   1140 gccaggccct gccctcacca agactgccca cgacagatgg ggcccaccct ca #accaatat   1200 cccccatccc tggtggggtt tcttcctctg gcttgagccg catgggtgct gt #gcctgtga   1260 tggtgcctgc ccagagtcaa gctggctctc tggtatgatg accccaccac tc #attggcta   1320 aaggatttgg ggtctctcct tcctataagg gtcacctcta gcacagaggc ct #gagtcatg   1380 ggaaagagtc acactcctga cccttagtac tctgccccca cctctcttta ct #gtgggaaa   1440 accatctcag taagacctaa gtgtccagga gacagaagga gaagaggaag tg #gatctgga   1500 attgggagga gcctccaccc acccctgact cctccttatg aagccagctg ct #gaaattag   1560 ctactcacca agagtgaggg gcagagactt ccagtcactg agtctcccag gc #ccccttga   1620 tctgtacccc acccctatct aacaccaccc ttggctccca ctccagctcc ct #gtattgat   1680 ataacctgtc aggctggctt ggttaggttt tactggggca gaggataggg aa #tctcttat   1740 taaaactaac atgaaatatg tgttgttttc atttgcaaat ttaaataaag at #acataatg   1800 tttgtatgaa aaa               #                   #                   #    1813 <210> SEQ ID NO 39 <211> LENGTH: 390 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 Met Ile Ser Leu Pro Gly Pro Leu Val Thr As #n Leu Leu Arg Phe Leu   1               5  #                 10  #                 15 Phe Leu Gly Leu Ser Ala Leu Ala Pro Pro Se #r Arg Ala Gln Leu Gln              20      #             25      #             30 Leu His Leu Pro Ala Asn Arg Leu Gln Ala Va #l Glu Gly Gly Glu Val          35          #         40          #         45 Val Leu Pro Ala Trp Tyr Thr Leu His Gly Gl #u Val Ser Ser Ser Gln      50              #     55              #     60 Pro Trp Glu Val Pro Phe Val Met Trp Phe Ph #e Lys Gln Lys Glu Lys  65                  # 70                  # 75                  # 80 Glu Asp Gln Val Leu Ser Tyr Ile Asn Gly Va #l Thr Thr Ser Lys Pro                  85  #                 90  #                 95 Gly Val Ser Leu Val Tyr Ser Met Pro Ser Ar #g Asn Leu Ser Leu Arg             100       #           105       #           110 Leu Glu Gly Leu Gln Glu Lys Asp Ser Gly Pr #o Tyr Ser Cys Ser Val         115           #       120           #       125 Asn Val Gln Asp Lys Gln Gly Lys Ser Arg Gl #y His Ser Ile Lys Thr     130               #   135               #   140 Leu Glu Leu Asn Val Leu Val Pro Pro Ala Pr #o Pro Ser Cys Arg Leu 145                 1 #50                 1 #55                 1 #60 Gln Gly Val Pro His Val Gly Ala Asn Val Th #r Leu Ser Cys Gln Ser                 165   #               170   #               175 Pro Arg Ser Lys Pro Ala Val Gln Tyr Gln Tr #p Asp Arg Gln Leu Pro             180       #           185       #           190 Ser Phe Gln Thr Phe Phe Ala Pro Ala Leu As #p Val Ile Arg Gly Ser         195           #       200           #       205 Leu Ser Leu Thr Asn Leu Ser Ser Ser Met Al #a Gly Val Tyr Val Cys     210               #   215               #   220 Lys Ala His Asn Glu Val Gly Thr Ala Gln Cy #s Asn Val Thr Leu Glu 225                 2 #30                 2 #35                 2 #40 Val Ser Thr Gly Pro Gly Ala Ala Val Val Al #a Gly Ala Val Val Gly                 245   #               250   #               255 Thr Leu Val Gly Leu Gly Leu Leu Ala Gly Le #u Val Leu Leu Tyr His             260       #           265       #           270 Arg Arg Gly Lys Ala Leu Glu Glu Pro Ala As #n Asp Ile Lys Glu Asp         275           #       280           #       285 Ala Ile Ala Pro Arg Thr Leu Pro Trp Pro Ly #s Ser Ser Asp Thr Ile     290               #   295               #   300 Ser Lys Asn Gly Thr Leu Ser Ser Val Thr Se #r Ala Arg Ala Leu Arg 305                 3 #10                 3 #15                 3 #20 Pro Pro His Gly Pro Pro Arg Pro Gly Ala Le #u Thr Pro Thr Pro Ser                 325   #               330   #               335 Leu Ser Ser Gln Ala Leu Pro Ser Pro Arg Le #u Pro Thr Thr Asp Gly             340       #           345       #           350 Ala His Pro Gln Pro Ile Ser Pro Ile Pro Gl #y Gly Val Ser Ser Ser         355           #       360           #       365 Gly Leu Ser Arg Met Gly Ala Val Pro Val Me #t Val Pro Ala Gln Ser     370               #   375               #   380 Gln Ala Gly Ser Leu Val 385                 3 #90 <210> SEQ ID NO 40 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 40 agggtctcca ggagaaagac tc            #                   #                 22 <210> SEQ ID NO 41 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 41 attgtgggcc ttgcagacat agac           #                   #                24 <210> SEQ ID NO 42 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 42 ggccacagca tcaaaacctt agaactcaat gtactggttc ctccagctcc   #              50 <210> SEQ ID NO 43 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 43 gtgtgacaca gcgtgggc              #                   #                   #  18 <210> SEQ ID NO 44 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 44 gaccggcagg cttctgcg              #                   #                   #  18 <210> SEQ ID NO 45 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 45 cagcagcttc agccaccagg agtgg           #                   #               25 <210> SEQ ID NO 46 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 46 ctgagccgtg ggctgcagtc tcgc           #                   #                24 <210> SEQ ID NO 47 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 47 ccgactacga ctggttcttc atcatgcagg atgacacata tgtgc    #                   #45 <210> SEQ ID NO 48 <211> LENGTH: 2822 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 cgccaccact gcggccaccg ccaatgaaac gcctcccgct cctagtggtt tt #ttccactt     60 tgttgaattg ttcctatact caaaattgca ccaagacacc ttgtctccca aa #tgcaaaat    120 gtgaaatacg caatggaatt gaagcctgct attgcaacat gggattttca gg #aaatggtg    180 tcacaatttg tgaagatgat aatgaatgtg gaaatttaac tcagtcctgt gg #cgaaaatg    240 ctaattgcac taacacagaa ggaagttatt attgtatgtg tgtacctggc tt #cagatcca    300 gcagtaacca agacaggttt atcactaatg atggaaccgt ctgtatagaa aa #tgtgaatg    360 caaactgcca tttagataat gtctgtatag ctgcaaatat taataaaact tt #aacaaaaa    420 tcagatccat aaaagaacct gtggctttgc tacaagaagt ctatagaaat tc #tgtgacag    480 atctttcacc aacagatata attacatata tagaaatatt agctgaatca tc #ttcattac    540 taggttacaa gaacaacact atctcagcca aggacaccct ttctaactca ac #tcttactg    600 aatttgtaaa aaccgtgaat aattttgttc aaagggatac atttgtagtt tg #ggacaagt    660 tatctgtgaa tcataggaga acacatctta caaaactcat gcacactgtt ga #acaagcta    720 ctttaaggat atcccagagc ttccaaaaga ccacagagtt tgatacaaat tc #aacggata    780 tagctctcaa agttttcttt tttgattcat ataacatgaa acatattcat cc #tcatatga    840 atatggatgg agactacata aatatatttc caaagagaaa agctgcatat ga #ttcaaatg    900 gcaatgttgc agttgcattt ttatattata agagtattgg tcctttgctt tc #atcatctg    960 acaacttctt attgaaacct caaaattatg ataattctga agaggaggaa ag #agtcatat   1020 cttcagtaat ttcagtctca atgagctcaa acccacccac attatatgaa ct #tgaaaaaa   1080 taacatttac attaagtcat cgaaaggtca cagataggta taggagtcta tg #tgcatttt   1140 ggaattactc acctgatacc atgaatggca gctggtcttc agagggctgt ga #gctgacat   1200 actcaaatga gacccacacc tcatgccgct gtaatcacct gacacatttt gc #aattttga   1260 tgtcctctgg tccttccatt ggtattaaag attataatat tcttacaagg at #cactcaac   1320 taggaataat tatttcactg atttgtcttg ccatatgcat ttttaccttc tg #gttcttca   1380 gtgaaattca aagcaccagg acaacaattc acaaaaatct ttgctgtagc ct #atttcttg   1440 ctgaacttgt ttttcttgtt gggatcaata caaatactaa taagctcttc tg #ttcaatca   1500 ttgccggact gctacactac ttctttttag ctgcttttgc atggatgtgc at #tgaaggca   1560 tacatctcta tctcattgtt gtgggtgtca tctacaacaa gggatttttg ca #caagaatt   1620 tttatatctt tggctatcta agcccagccg tggtagttgg attttcggca gc #actaggat   1680 acagatatta tggcacaacc aaagtatgtt ggcttagcac cgaaaacaac tt #tatttgga   1740 gttttatagg accagcatgc ctaatcattc ttgttaatct cttggctttt gg #agtcatca   1800 tatacaaagt ttttcgtcac actgcagggt tgaaaccaga agttagttgc tt #tgagaaca   1860 taaggtcttg tgcaagagga gccctcgctc ttctgttcct tctcggcacc ac #ctggatct   1920 ttggggttct ccatgttgtg cacgcatcag tggttacagc ttacctcttc ac #agtcagca   1980 atgctttcca ggggatgttc atttttttat tcctgtgtgt tttatctaga aa #gattcaag   2040 aagaatatta cagattgttc aaaaatgtcc cctgttgttt tggatgttta ag #gtaaacat   2100 agagaatggt ggataattac aactgcacaa aaataaaaat tccaagctgt gg #atgaccaa   2160 tgtataaaaa tgactcatca aattatccaa ttattaacta ctagacaaaa ag #tattttaa   2220 atcagttttt ctgtttatgc tataggaact gtagataata aggtaaaatt at #gtatcata   2280 tagatatact atgtttttct atgtgaaata gttctgtcaa aaatagtatt gc #agatattt   2340 ggaaagtaat tggtttctca ggagtgatat cactgcaccc aaggaaagat tt #tctttcta   2400 acacgagaag tatatgaatg tcctgaagga aaccactggc ttgatatttc tg #tgactcgt   2460 gttgcctttg aaactagtcc cctaccacct cggtaatgag ctccattaca ga #aagtggaa   2520 cataagagaa tgaaggggca gaatatcaaa cagtgaaaag ggaatgataa ga #tgtatttt   2580 gaatgaactg ttttttctgt agactagctg agaaattgtt gacataaaat aa #agaattga   2640 agaaacacat tttaccattt tgtgaattgt tctgaactta aatgtccact aa #aacaactt   2700 agacttctgt ttgctaaatc tgtttctttt tctaatattc taaaaaaaaa aa #aaaggttt   2760 acctccacaa attgaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa #aaaaaaaa   2820 aa                   #                   #                   #            2822 <210> SEQ ID NO 49 <211> LENGTH: 690 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 49 Met Lys Arg Leu Pro Leu Leu Val Val Phe Se #r Thr Leu Leu Asn Cys   1               5  #                 10  #                 15 Ser Tyr Thr Gln Asn Cys Thr Lys Thr Pro Cy #s Leu Pro Asn Ala Lys              20      #             25      #             30 Cys Glu Ile Arg Asn Gly Ile Glu Ala Cys Ty #r Cys Asn Met Gly Phe          35          #         40          #         45 Ser Gly Asn Gly Val Thr Ile Cys Glu Asp As #p Asn Glu Cys Gly Asn      50              #     55              #     60 Leu Thr Gln Ser Cys Gly Glu Asn Ala Asn Cy #s Thr Asn Thr Glu Gly  65                  # 70                  # 75                  # 80 Ser Tyr Tyr Cys Met Cys Val Pro Gly Phe Ar #g Ser Ser Ser Asn Gln                  85  #                 90  #                 95 Asp Arg Phe Ile Thr Asn Asp Gly Thr Val Cy #s Ile Glu Asn Val Asn             100       #           105       #           110 Ala Asn Cys His Leu Asp Asn Val Cys Ile Al #a Ala Asn Ile Asn Lys         115           #       120           #       125 Thr Leu Thr Lys Ile Arg Ser Ile Lys Glu Pr #o Val Ala Leu Leu Gln     130               #   135               #   140 Glu Val Tyr Arg Asn Ser Val Thr Asp Leu Se #r Pro Thr Asp Ile Ile 145                 1 #50                 1 #55                 1 #60 Thr Tyr Ile Glu Ile Leu Ala Glu Ser Ser Se #r Leu Leu Gly Tyr Lys                 165   #               170   #               175 Asn Asn Thr Ile Ser Ala Lys Asp Thr Leu Se #r Asn Ser Thr Leu Thr             180       #           185       #           190 Glu Phe Val Lys Thr Val Asn Asn Phe Val Gl #n Arg Asp Thr Phe Val         195           #       200           #       205 Val Trp Asp Lys Leu Ser Val Asn His Arg Ar #g Thr His Leu Thr Lys     210               #   215               #   220 Leu Met His Thr Val Glu Gln Ala Thr Leu Ar #g Ile Ser Gln Ser Phe 225                 2 #30                 2 #35                 2 #40 Gln Lys Thr Thr Glu Phe Asp Thr Asn Ser Th #r Asp Ile Ala Leu Lys                 245   #               250   #               255 Val Phe Phe Phe Asp Ser Tyr Asn Met Lys Hi #s Ile His Pro His Met             260       #           265       #           270 Asn Met Asp Gly Asp Tyr Ile Asn Ile Phe Pr #o Lys Arg Lys Ala Ala         275           #       280           #       285 Tyr Asp Ser Asn Gly Asn Val Ala Val Ala Ph #e Leu Tyr Tyr Lys Ser     290               #   295               #   300 Ile Gly Pro Leu Leu Ser Ser Ser Asp Asn Ph #e Leu Leu Lys Pro Gln 305                 3 #10                 3 #15                 3 #20 Asn Tyr Asp Asn Ser Glu Glu Glu Glu Arg Va #l Ile Ser Ser Val Ile                 325   #               330   #               335 Ser Val Ser Met Ser Ser Asn Pro Pro Thr Le #u Tyr Glu Leu Glu Lys             340       #           345       #           350 Ile Thr Phe Thr Leu Ser His Arg Lys Val Th #r Asp Arg Tyr Arg Ser         355           #       360           #       365 Leu Cys Ala Phe Trp Asn Tyr Ser Pro Asp Th #r Met Asn Gly Ser Trp     370               #   375               #   380 Ser Ser Glu Gly Cys Glu Leu Thr Tyr Ser As #n Glu Thr His Thr Ser 385                 3 #90                 3 #95                 4 #00 Cys Arg Cys Asn His Leu Thr His Phe Ala Il #e Leu Met Ser Ser Gly                 405   #               410   #               415 Pro Ser Ile Gly Ile Lys Asp Tyr Asn Ile Le #u Thr Arg Ile Thr Gln             420       #           425       #           430 Leu Gly Ile Ile Ile Ser Leu Ile Cys Leu Al #a Ile Cys Ile Phe Thr         435           #       440           #       445 Phe Trp Phe Phe Ser Glu Ile Gln Ser Thr Ar #g Thr Thr Ile His Lys     450               #   455               #   460 Asn Leu Cys Cys Ser Leu Phe Leu Ala Glu Le #u Val Phe Leu Val Gly 465                 4 #70                 4 #75                 4 #80 Ile Asn Thr Asn Thr Asn Lys Leu Phe Cys Se #r Ile Ile Ala Gly Leu                 485   #               490   #               495 Leu His Tyr Phe Phe Leu Ala Ala Phe Ala Tr #p Met Cys Ile Glu Gly             500       #           505       #           510 Ile His Leu Tyr Leu Ile Val Val Gly Val Il #e Tyr Asn Lys Gly Phe         515           #       520           #       525 Leu His Lys Asn Phe Tyr Ile Phe Gly Tyr Le #u Ser Pro Ala Val Val     530               #   535               #   540 Val Gly Phe Ser Ala Ala Leu Gly Tyr Arg Ty #r Tyr Gly Thr Thr Lys 545                 5 #50                 5 #55                 5 #60 Val Cys Trp Leu Ser Thr Glu Asn Asn Phe Il #e Trp Ser Phe Ile Gly                 565   #               570   #               575 Pro Ala Cys Leu Ile Ile Leu Val Asn Leu Le #u Ala Phe Gly Val Ile             580       #           585       #           590 Ile Tyr Lys Val Phe Arg His Thr Ala Gly Le #u Lys Pro Glu Val Ser         595           #       600           #       605 Cys Phe Glu Asn Ile Arg Ser Cys Ala Arg Gl #y Ala Leu Ala Leu Leu     610               #   615               #   620 Phe Leu Leu Gly Thr Thr Trp Ile Phe Gly Va #l Leu His Val Val His 625                 6 #30                 6 #35                 6 #40 Ala Ser Val Val Thr Ala Tyr Leu Phe Thr Va #l Ser Asn Ala Phe Gln                 645   #               650   #               655 Gly Met Phe Ile Phe Leu Phe Leu Cys Val Le #u Ser Arg Lys Ile Gln             660       #           665       #           670 Glu Glu Tyr Tyr Arg Leu Phe Lys Asn Val Pr #o Cys Cys Phe Gly Cys         675           #       680           #       685 Leu Arg     690 <210> SEQ ID NO 50 <211> LENGTH: 589 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (61) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 50 tggaaacata tcctccctca tatgaatatg gatggagact acataaatat at #ttccaaag     60 ngaaaagccg gcatatggat tcaaatggca atgttgcagt tgcattttta ta #ttataaga    120 gtattggtcc ctttgctttc atcatctgac aacttcttat tgaaacctca aa #attatgat    180 aattctgaag aggaggaaag agtcatatct tcagtaattt cagtctcaat ga #gctcaaac    240 ccacccacat tatatgaact tgaaaaaata acatttacat taagtcatcg aa #aggtcaca    300 gataggtata ggagtctatg tggcattttg gaatactcac ctgataccat ga #atggcagc    360 tggtcttcag agggctgtga gctgacatac tcaaatgaga cccacacctc at #gccgctgt    420 aatcacctga cacattttgc aattttgatg tcctctggtc cttccattgg ta #ttaaagat    480 tataatattc ttacaaggat cactcaacta ggaataatta tttcactgat tt #gtcttgcc    540 atatgcattt ttaccttctg gttcttcagt gaaattcaaa gcaccagga   #              589 <210> SEQ ID NO 51 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 51 ggtaatgagc tccattacag             #                   #                   # 20 <210> SEQ ID NO 52 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 52 ggagtagaaa gcgcatgg              #                   #                   #  18 <210> SEQ ID NO 53 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 53 cacctgatac catgaatggc ag            #                   #                 22 <210> SEQ ID NO 54 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 54 cgagctcgaa ttaattcg              #                   #                   #  18 <210> SEQ ID NO 55 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 55 ggatctcctg agctcagg              #                   #                   #  18 <210> SEQ ID NO 56 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 56 cctagttgag tgatccttgt aag            #                   #                23 <210> SEQ ID NO 57 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 57 atgagaccca cacctcatgc cgctgtaatc acctgacaca ttttgcaatt   #              50 <210> SEQ ID NO 58 <211> LENGTH: 2137 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 58 gctcccagcc aagaacctcg gggccgctgc gcggtgggga ggagttcccc ga #aacccggc     60 cgctaagcga ggcctcctcc tcccgcagat ccgaacggcc tgggcggggt ca #ccccggct    120 gggacaagaa gccgccgcct gcctgcccgg gcccggggag ggggctgggg ct #ggggccgg    180 aggcggggtg tgagtgggtg tgtgcggggg gcggaggctt gatgcaatcc cg #ataagaaa    240 tgctcgggtg tcttgggcac ctacccgtgg ggcccgtaag gcgctactat at #aaggctgc    300 cggcccggag ccgccgcgcc gtcagagcag gagcgctgcg tccaggatct ag #ggccacga    360 ccatcccaac ccggcactca cagccccgca gcgcatcccg gtcgccgccc ag #cctcccgc    420 acccccatcg ccggagctgc gccgagagcc ccagggaggt gccatgcgga gc #gggtgtgt    480 ggtggtccac gtatggatcc tggccggcct ctggctggcc gtggccgggc gc #cccctcgc    540 cttctcggac gcggggcccc acgtgcacta cggctggggc gaccccatcc gc #ctgcggca    600 cctgtacacc tccggccccc acgggctctc cagctgcttc ctgcgcatcc gt #gccgacgg    660 cgtcgtggac tgcgcgcggg gccagagcgc gcacagtttg ctggagatca ag #gcagtcgc    720 tctgcggacc gtggccatca agggcgtgca cagcgtgcgg tacctctgca tg #ggcgccga    780 cggcaagatg caggggctgc ttcagtactc ggaggaagac tgtgctttcg ag #gaggagat    840 ccgcccagat ggctacaatg tgtaccgatc cgagaagcac cgcctcccgg tc #tccctgag    900 cagtgccaaa cagcggcagc tgtacaagaa cagaggcttt cttccactct ct #catttcct    960 gcccatgctg cccatggtcc cagaggagcc tgaggacctc aggggccact tg #gaatctga   1020 catgttctct tcgcccctgg agaccgacag catggaccca tttgggcttg tc #accggact   1080 ggaggccgtg aggagtccca gctttgagaa gtaactgaga ccatgcccgg gc #ctcttcac   1140 tgctgccagg ggctgtggta cctgcagcgt gggggacgtg cttctacaag aa #cagtcctg   1200 agtccacgtt ctgtttagct ttaggaagaa acatctagaa gttgtacata tt #cagagttt   1260 tccattggca gtgccagttt ctagccaata gacttgtctg atcataacat tg #taagcctg   1320 tagcttgccc agctgctgcc tgggccccca ttctgctccc tcgaggttgc tg #gacaagct   1380 gctgcactgt ctcagttctg cttgaatacc tccatcgatg gggaactcac tt #cctttgga   1440 aaaattctta tgtcaagctg aaattctcta attttttctc atcacttccc ca #ggagcagc   1500 cagaagacag gcagtagttt taatttcagg aacaggtgat ccactctgta aa #acagcagg   1560 taaatttcac tcaaccccat gtgggaattg atctatatct ctacttccag gg #accatttg   1620 cccttcccaa atccctccag gccagaactg actggagcag gcatggccca cc #aggcttca   1680 ggagtagggg aagcctggag ccccactcca gccctgggac aacttgagaa tt #ccccctga   1740 ggccagttct gtcatggatg ctgtcctgag aataacttgc tgtcccggtg tc #acctgctt   1800 ccatctccca gcccaccagc cctctgccca cctcacatgc ctccccatgg at #tggggcct   1860 cccaggcccc ccaccttatg tcaacctgca cttcttgttc aaaaatcagg aa #aagaaaag   1920 atttgaagac cccaagtctt gtcaataact tgctgtgtgg aagcagcggg gg #aagaccta   1980 gaaccctttc cccagcactt ggttttccaa catgatattt atgagtaatt ta #ttttgata   2040 tgtacatctc ttattttctt acattattta tgcccccaaa ttatatttat gt #atgtaagt   2100 gaggtttgtt ttgtatatta aaatggagtt tgtttgt       #                   #    2137 <210> SEQ ID NO 59 <211> LENGTH: 216 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 Met Arg Ser Gly Cys Val Val Val His Val Tr #p Ile Leu Ala Gly Leu   1               5  #                 10  #                 15 Trp Leu Ala Val Ala Gly Arg Pro Leu Ala Ph #e Ser Asp Ala Gly Pro              20      #             25      #             30 His Val His Tyr Gly Trp Gly Asp Pro Ile Ar #g Leu Arg His Leu Tyr          35          #         40          #         45 Thr Ser Gly Pro His Gly Leu Ser Ser Cys Ph #e Leu Arg Ile Arg Ala      50              #     55              #     60 Asp Gly Val Val Asp Cys Ala Arg Gly Gln Se #r Ala His Ser Leu Leu  65                  # 70                  # 75                  # 80 Glu Ile Lys Ala Val Ala Leu Arg Thr Val Al #a Ile Lys Gly Val His                  85  #                 90  #                 95 Ser Val Arg Tyr Leu Cys Met Gly Ala Asp Gl #y Lys Met Gln Gly Leu             100       #           105       #           110 Leu Gln Tyr Ser Glu Glu Asp Cys Ala Phe Gl #u Glu Glu Ile Arg Pro         115           #       120           #       125 Asp Gly Tyr Asn Val Tyr Arg Ser Glu Lys Hi #s Arg Leu Pro Val Ser     130               #   135               #   140 Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Ly #s Asn Arg Gly Phe Leu 145                 1 #50                 1 #55                 1 #60 Pro Leu Ser His Phe Leu Pro Met Leu Pro Me #t Val Pro Glu Glu Pro                 165   #               170   #               175 Glu Asp Leu Arg Gly His Leu Glu Ser Asp Me #t Phe Ser Ser Pro Leu             180       #           185       #           190 Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Va #l Thr Gly Leu Glu Ala         195           #       200           #       205 Val Arg Ser Pro Ser Phe Glu Lys     210               #   215 <210> SEQ ID NO 60 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 60 atccgcccag atggctacaa tgtgta           #                   #              26 <210> SEQ ID NO 61 <211> LENGTH: 42 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 61 gcctcccggt ctccctgagc agtgccaaac agcggcagtg ta     #                   #  42 <210> SEQ ID NO 62 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 62 ccagtccggt gacaagccca aa            #                   #                 22 <210> SEQ ID NO 63 <211> LENGTH: 1295 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 cccagaagtt caagggcccc cggcctcctg cgctcctgcc gccgggaccc tc #gacctcct     60 cagagcagcc ggctgccgcc ccgggaagat ggcgaggagg agccgccacc gc #ctcctcct    120 gctgctgctg cgctacctgg tggtcgccct gggctatcat aaggcctatg gg #ttttctgc    180 cccaaaagac caacaagtag tcacagcagt agagtaccaa gaggctattt ta #gcctgcaa    240 aaccccaaag aagactgttt cctccagatt agagtggaag aaactgggtc gg #agtgtctc    300 ctttgtctac tatcaacaga ctcttcaagg tgattttaaa aatcgagctg ag #atgataga    360 tttcaatatc cggatcaaaa atgtgacaag aagtgatgcg gggaaatatc gt #tgtgaagt    420 tagtgcccca tctgagcaag gccaaaacct ggaagaggat acagtcactc tg #gaagtatt    480 agtggctcca gcagttccat catgtgaagt accctcttct gctctgagtg ga #actgtggt    540 agagctacga tgtcaagaca aagaagggaa tccagctcct gaatacacat gg #tttaagga    600 tggcatccgt ttgctagaaa atcccagact tggctcccaa agcaccaaca gc #tcatacac    660 aatgaataca aaaactggaa ctctgcaatt taatactgtt tccaaactgg ac #actggaga    720 atattcctgt gaagcccgca attctgttgg atatcgcagg tgtcctggga aa #cgaatgca    780 agtagatgat ctcaacataa gtggcatcat agcagccgta gtagttgtgg cc #ttagtgat    840 ttccgtttgt ggccttggtg tatgctatgc tcagaggaaa ggctactttt ca #aaagaaac    900 ctccttccag aagagtaatt cttcatctaa agccacgaca atgagtgaaa at #gtgcagtg    960 gctcacgcct gtaatcccag cactttggaa ggccgcggcg ggcggatcac ga #ggtcagga   1020 gttctagacc agtctggcca atatggtgaa accccatctc tactaaaata ca #aaaattag   1080 ctgggcatgg tggcatgtgc ctgcagttcc agctgcttgg gagacaggag aa #tcacttga   1140 acccgggagg cggaggttgc agtgagctga gatcacgcca ctgcagtcca gc #ctgggtaa   1200 cagagcaaga ttccatctca aaaaataaaa taaataaata aataaatact gg #tttttacc   1260 tgtagaattc ttacaataaa tatagcttga tattc        #                   #     1295 <210> SEQ ID NO 64 <211> LENGTH: 312 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 64 Met Ala Arg Arg Ser Arg His Arg Leu Leu Le #u Leu Leu Leu Arg Tyr   1               5  #                 10  #                 15 Leu Val Val Ala Leu Gly Tyr His Lys Ala Ty #r Gly Phe Ser Ala Pro              20      #             25      #             30 Lys Asp Gln Gln Val Val Thr Ala Val Glu Ty #r Gln Glu Ala Ile Leu          35          #         40          #         45 Ala Cys Lys Thr Pro Lys Lys Thr Val Ser Se #r Arg Leu Glu Trp Lys      50              #     55              #     60 Lys Leu Gly Arg Ser Val Ser Phe Val Tyr Ty #r Gln Gln Thr Leu Gln  65                  # 70                  # 75                  # 80 Gly Asp Phe Lys Asn Arg Ala Glu Met Ile As #p Phe Asn Ile Arg Ile                  85  #                 90  #                 95 Lys Asn Val Thr Arg Ser Asp Ala Gly Lys Ty #r Arg Cys Glu Val Ser             100       #           105       #           110 Ala Pro Ser Glu Gln Gly Gln Asn Leu Glu Gl #u Asp Thr Val Thr Leu         115           #       120           #       125 Glu Val Leu Val Ala Pro Ala Val Pro Ser Cy #s Glu Val Pro Ser Ser     130               #   135               #   140 Ala Leu Ser Gly Thr Val Val Glu Leu Arg Cy #s Gln Asp Lys Glu Gly 145                 1 #50                 1 #55                 1 #60 Asn Pro Ala Pro Glu Tyr Thr Trp Phe Lys As #p Gly Ile Arg Leu Leu                 165   #               170   #               175 Glu Asn Pro Arg Leu Gly Ser Gln Ser Thr As #n Ser Ser Tyr Thr Met             180       #           185       #           190 Asn Thr Lys Thr Gly Thr Leu Gln Phe Asn Th #r Val Ser Lys Leu Asp         195           #       200           #       205 Thr Gly Glu Tyr Ser Cys Glu Ala Arg Asn Se #r Val Gly Tyr Arg Arg     210               #   215               #   220 Cys Pro Gly Lys Arg Met Gln Val Asp Asp Le #u Asn Ile Ser Gly Ile 225                 2 #30                 2 #35                 2 #40 Ile Ala Ala Val Val Val Val Ala Leu Val Il #e Ser Val Cys Gly Leu                 245   #               250   #               255 Gly Val Cys Tyr Ala Gln Arg Lys Gly Tyr Ph #e Ser Lys Glu Thr Ser             260       #           265       #           270 Phe Gln Lys Ser Asn Ser Ser Ser Lys Ala Th #r Thr Met Ser Glu Asn         275           #       280           #       285 Val Gln Trp Leu Thr Pro Val Ile Pro Ala Le #u Trp Lys Ala Ala Ala     290               #   295               #   300 Gly Gly Ser Arg Gly Gln Glu Phe 305                 3 #10 <210> SEQ ID NO 65 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 65 atcgttgtga agttagtgcc cc            #                   #                 22 <210> SEQ ID NO 66 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 66 acctgcgata tccaacagaa ttg            #                   #                23 <210> SEQ ID NO 67 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 67 ggaagaggat acagtcactc tggaagtatt agtggctcca gcagttcc   #                48 <210> SEQ ID NO 68 <211> LENGTH: 2639 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 gacatcggag gtgggctagc actgaaactg cttttcaaga cgaggaagag ga #ggagaaag     60 agaaagaaga ggaagatgtt gggcaacatt tatttaacat gctccacagc cc #ggaccctg    120 gcatcatgct gctattcctg caaatactga agaagcatgg gatttaaata tt #ttacttct    180 aaataaatga attactcaat ctcctatgac catctataca tactccacct tc #aaaaagta    240 catcaatatt atatcattaa ggaaatagta accttctctt ctccaatatg ca #tgacattt    300 ttggacaatg caattgtggc actggcactt atttcagtga agaaaaactt tg #tggttcta    360 tggcattcat catttgacaa atgcaagcat cttccttatc aatcagctcc ta #ttgaactt    420 actagcactg actgtggaat ccttaagggc ccattacatt tctgaagaag aa #agctaaga    480 tgaaggacat gccactccga attcatgtgc tacttggcct agctatcact ac #actagtac    540 aagctgtaga taaaaaagtg gattgtccac ggttatgtac gtgtgaaatc ag #gccttggt    600 ttacacccag atccatttat atggaagcat ctacagtgga ttgtaatgat tt #aggtcttt    660 taactttccc agccagattg ccagctaaca cacagattct tctcctacag ac #taacaata    720 ttgcaaaaat tgaatactcc acagactttc cagtaaacct tactggcctg ga #tttatctc    780 aaaacaattt atcttcagtc accaatatta atgtaaaaaa gatgcctcag ct #cctttctg    840 tgtacctaga ggaaaacaaa cttactgaac tgcctgaaaa atgtctgtcc ga #actgagca    900 acttacaaga actctatatt aatcacaact tgctttctac aatttcacct gg #agccttta    960 ttggcctaca taatcttctt cgacttcatc tcaattcaaa tagattgcag at #gatcaaca   1020 gtaagtggtt tgatgctctt ccaaatctag agattctgat gattggggaa aa #tccaatta   1080 tcagaatcaa agacatgaac tttaagcctc ttatcaatct tcgcagcctg gt #tatagctg   1140 gtataaacct cacagaaata ccagataacg ccttggttgg actggaaaac tt #agaaagca   1200 tctcttttta cgataacagg cttattaaag taccccatgt tgctcttcaa aa #agttgtaa   1260 atctcaaatt tttggatcta aataaaaatc ctattaatag aatacgaagg gg #tgatttta   1320 gcaatatgct acacttaaaa gagttgggga taaataatat gcctgagctg at #ttccatcg   1380 atagtcttgc tgtggataac ctgccagatt taagaaaaat agaagctact aa #caacccta   1440 gattgtctta cattcacccc aatgcatttt tcagactccc caagctggaa tc #actcatgc   1500 tgaacagcaa tgctctcagt gccctgtacc atggtaccat tgagtctctg cc #aaacctca   1560 aggaaatcag catacacagt aaccccatca ggtgtgactg tgtcatccgt tg #gatgaaca   1620 tgaacaaaac caacattcga ttcatggagc cagattcact gttttgcgtg ga #cccacctg   1680 aattccaagg tcagaatgtt cggcaagtgc atttcaggga catgatggaa at #ttgtctcc   1740 ctcttatagc tcctgagagc tttccttcta atctaaatgt agaagctggg ag #ctatgttt   1800 cctttcactg tagagctact gcagaaccac agcctgaaat ctactggata ac #accttctg   1860 gtcaaaaact cttgcctaat accctgacag acaagttcta tgtccattct ga #gggaacac   1920 tagatataaa tggcgtaact cccaaagaag ggggtttata tacttgtata gc #aactaacc   1980 tagttggcgc tgacttgaag tctgttatga tcaaagtgga tggatctttt cc #acaagata   2040 acaatggctc tttgaatatt aaaataagag atattcaggc caattcagtt tt #ggtgtcct   2100 ggaaagcaag ttctaaaatt ctcaaatcta gtgttaaatg gacagccttt gt #caagactg   2160 aaaattctca tgctgcgcaa agtgctcgaa taccatctga tgtcaaggta ta #taatctta   2220 ctcatctgaa tccatcaact gagtataaaa tttgtattga tattcccacc at #ctatcaga   2280 aaaacagaaa aaaatgtgta aatgtcacca ccaaaggttt gcaccctgat ca #aaaagagt   2340 atgaaaagaa taataccaca acacttatgg cctgtcttgg aggccttctg gg #gattattg   2400 gtgtgatatg tcttatcagc tgcctctctc cagaaatgaa ctgtgatggt gg #acacagct   2460 atgtgaggaa ttacttacag aaaccaacct ttgcattagg tgagctttat cc #tcctctga   2520 taaatctctg ggaagcagga aaagaaaaaa gtacatcact gaaagtaaaa gc #aactgtta   2580 taggtttacc aacaaatatg tcctaaaaac caccaaggaa acctactcca aa #aatgaac    2639 <210> SEQ ID NO 69 <211> LENGTH: 708 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 69 Met Lys Asp Met Pro Leu Arg Ile His Val Le #u Leu Gly Leu Ala Ile   1               5  #                 10  #                 15 Thr Thr Leu Val Gln Ala Val Asp Lys Lys Va #l Asp Cys Pro Arg Leu              20      #             25      #             30 Cys Thr Cys Glu Ile Arg Pro Trp Phe Thr Pr #o Arg Ser Ile Tyr Met          35          #         40          #         45 Glu Ala Ser Thr Val Asp Cys Asn Asp Leu Gl #y Leu Leu Thr Phe Pro      50              #     55              #     60 Ala Arg Leu Pro Ala Asn Thr Gln Ile Leu Le #u Leu Gln Thr Asn Asn  65                  # 70                  # 75                  # 80 Ile Ala Lys Ile Glu Tyr Ser Thr Asp Phe Pr #o Val Asn Leu Thr Gly                  85  #                 90  #                 95 Leu Asp Leu Ser Gln Asn Asn Leu Ser Ser Va #l Thr Asn Ile Asn Val             100       #           105       #           110 Lys Lys Met Pro Gln Leu Leu Ser Val Tyr Le #u Glu Glu Asn Lys Leu         115           #       120           #       125 Thr Glu Leu Pro Glu Lys Cys Leu Ser Glu Le #u Ser Asn Leu Gln Glu     130               #   135               #   140 Leu Tyr Ile Asn His Asn Leu Leu Ser Thr Il #e Ser Pro Gly Ala Phe 145                 1 #50                 1 #55                 1 #60 Ile Gly Leu His Asn Leu Leu Arg Leu His Le #u Asn Ser Asn Arg Leu                 165   #               170   #               175 Gln Met Ile Asn Ser Lys Trp Phe Asp Ala Le #u Pro Asn Leu Glu Ile             180       #           185       #           190 Leu Met Ile Gly Glu Asn Pro Ile Ile Arg Il #e Lys Asp Met Asn Phe         195           #       200           #       205 Lys Pro Leu Ile Asn Leu Arg Ser Leu Val Il #e Ala Gly Ile Asn Leu     210               #   215               #   220 Thr Glu Ile Pro Asp Asn Ala Leu Val Gly Le #u Glu Asn Leu Glu Ser 225                 2 #30                 2 #35                 2 #40 Ile Ser Phe Tyr Asp Asn Arg Leu Ile Lys Va #l Pro His Val Ala Leu                 245   #               250   #               255 Gln Lys Val Val Asn Leu Lys Phe Leu Asp Le #u Asn Lys Asn Pro Ile             260       #           265       #           270 Asn Arg Ile Arg Arg Gly Asp Phe Ser Asn Me #t Leu His Leu Lys Glu         275           #       280           #       285 Leu Gly Ile Asn Asn Met Pro Glu Leu Ile Se #r Ile Asp Ser Leu Ala     290               #   295               #   300 Val Asp Asn Leu Pro Asp Leu Arg Lys Ile Gl #u Ala Thr Asn Asn Pro 305                 3 #10                 3 #15                 3 #20 Arg Leu Ser Tyr Ile His Pro Asn Ala Phe Ph #e Arg Leu Pro Lys Leu                 325   #               330   #               335 Glu Ser Leu Met Leu Asn Ser Asn Ala Leu Se #r Ala Leu Tyr His Gly             340       #           345       #           350 Thr Ile Glu Ser Leu Pro Asn Leu Lys Glu Il #e Ser Ile His Ser Asn         355           #       360           #       365 Pro Ile Arg Cys Asp Cys Val Ile Arg Trp Me #t Asn Met Asn Lys Thr     370               #   375               #   380 Asn Ile Arg Phe Met Glu Pro Asp Ser Leu Ph #e Cys Val Asp Pro Pro 385                 3 #90                 3 #95                 4 #00 Glu Phe Gln Gly Gln Asn Val Arg Gln Val Hi #s Phe Arg Asp Met Met                 405   #               410   #               415 Glu Ile Cys Leu Pro Leu Ile Ala Pro Glu Se #r Phe Pro Ser Asn Leu             420       #           425       #           430 Asn Val Glu Ala Gly Ser Tyr Val Ser Phe Hi #s Cys Arg Ala Thr Ala         435           #       440           #       445 Glu Pro Gln Pro Glu Ile Tyr Trp Ile Thr Pr #o Ser Gly Gln Lys Leu     450               #   455               #   460 Leu Pro Asn Thr Leu Thr Asp Lys Phe Tyr Va #l His Ser Glu Gly Thr 465                 4 #70                 4 #75                 4 #80 Leu Asp Ile Asn Gly Val Thr Pro Lys Glu Gl #y Gly Leu Tyr Thr Cys                 485   #               490   #               495 Ile Ala Thr Asn Leu Val Gly Ala Asp Leu Ly #s Ser Val Met Ile Lys             500       #           505       #           510 Val Asp Gly Ser Phe Pro Gln Asp Asn Asn Gl #y Ser Leu Asn Ile Lys         515           #       520           #       525 Ile Arg Asp Ile Gln Ala Asn Ser Val Leu Va #l Ser Trp Lys Ala Ser     530               #   535               #   540 Ser Lys Ile Leu Lys Ser Ser Val Lys Trp Th #r Ala Phe Val Lys Thr 545                 5 #50                 5 #55                 5 #60 Glu Asn Ser His Ala Ala Gln Ser Ala Arg Il #e Pro Ser Asp Val Lys                 565   #               570   #               575 Val Tyr Asn Leu Thr His Leu Asn Pro Ser Th #r Glu Tyr Lys Ile Cys             580       #           585       #           590 Ile Asp Ile Pro Thr Ile Tyr Gln Lys Asn Ar #g Lys Lys Cys Val Asn         595           #       600           #       605 Val Thr Thr Lys Gly Leu His Pro Asp Gln Ly #s Glu Tyr Glu Lys Asn     610               #   615               #   620 Asn Thr Thr Thr Leu Met Ala Cys Leu Gly Gl #y Leu Leu Gly Ile Ile 625                 6 #30                 6 #35                 6 #40 Gly Val Ile Cys Leu Ile Ser Cys Leu Ser Pr #o Glu Met Asn Cys Asp                 645   #               650   #               655 Gly Gly His Ser Tyr Val Arg Asn Tyr Leu Gl #n Lys Pro Thr Phe Ala             660       #           665       #           670 Leu Gly Glu Leu Tyr Pro Pro Leu Ile Asn Le #u Trp Glu Ala Gly Lys         675           #       680           #       685 Glu Lys Ser Thr Ser Leu Lys Val Lys Ala Th #r Val Ile Gly Leu Pro     690               #   695               #   700 Thr Asn Met Ser 705 <210> SEQ ID NO 70 <211> LENGTH: 1305 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 70 gcccgggact ggcgcaaggt gcccaagcaa ggaaagaaat aatgaagaga ca #catgtgtt     60 agctgcagcc ttttgaaaca cgcaagaagg aaatcaatag tgtggacagg gc #tggaacct    120 ttaccacgct tgttggagta gatgaggaat gggctcgtga ttatgctgac at #tccagcat    180 gaatctggta gacctgtggt taacccgttc cctctccatg tgtctcctcc ta #caaagttt    240 tgttcttatg atactgtgct ttcattctgc cagtatgtgt cccaagggct gt #ctttgttc    300 ttcctctggg ggtttaaatg tcacctgtag caatgcaaat ctcaaggaaa ta #cctagaga    360 tcttcctcct gaaacagtct tactgtatct ggactccaat cagatcacat ct #attcccaa    420 tgaaattttt aaggacctcc atcaactgag agttctcaac ctgtccaaaa at #ggcattga    480 gtttatcgat gagcatgcct tcaaaggagt agctgaaacc ttgcagactc tg #gacttgtc    540 cgacaatcgg attcaaagtg tgcacaaaaa tgccttcaat aacctgaagg cc #agggccag    600 aattgccaac aacccctggc actgcgactg tactctacag caagttctga gg #agcatggc    660 gtccaatcat gagacagccc acaacgtgat ctgtaaaacg tccgtgttgg at #gaacatgc    720 tggcagacca ttcctcaatg ctgccaacga cgctgacctt tgtaacctcc ct #aaaaaaac    780 taccgattat gccatgctgg tcaccatgtt tggctggttc actatggtga tc #tcatatgt    840 ggtatattat gtgaggcaaa atcaggagga tgcccggaga cacctcgaat ac #ttgaaatc    900 cctgccaagc aggcagaaga aagcagatga acctgatgat attagcactg tg #gtatagtg    960 tccaaactga ctgtcattga gaaagaaaga aagtagtttg cgattgcagt ag #aaataagt   1020 ggtttacttc tcccatccat tgtaaacatt tgaaactttg tatttcagtt tt #ttttgaat   1080 tatgccactg ctgaactttt aacaaacact acaacataaa taatttgagt tt #aggtgatc   1140 caccccttaa ttgtaccccc gatggtatat ttctgagtaa gctactatct ga #acattagt   1200 tagatccatc tcactattta ataatgaaat ttattttttt aatttaaaag ca #aataaaag   1260 cttaactttg aaccatggga aaaaaaaaaa aaaaaaaaaa aaaca    #                1305 <210> SEQ ID NO 71 <211> LENGTH: 259 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71 Met Asn Leu Val Asp Leu Trp Leu Thr Arg Se #r Leu Ser Met Cys Leu   1               5  #                 10  #                 15 Leu Leu Gln Ser Phe Val Leu Met Ile Leu Cy #s Phe His Ser Ala Ser              20      #             25      #             30 Met Cys Pro Lys Gly Cys Leu Cys Ser Ser Se #r Gly Gly Leu Asn Val          35          #         40          #         45 Thr Cys Ser Asn Ala Asn Leu Lys Glu Ile Pr #o Arg Asp Leu Pro Pro      50              #     55              #     60 Glu Thr Val Leu Leu Tyr Leu Asp Ser Asn Gl #n Ile Thr Ser Ile Pro  65                  # 70                  # 75                  # 80 Asn Glu Ile Phe Lys Asp Leu His Gln Leu Ar #g Val Leu Asn Leu Ser                  85  #                 90  #                 95 Lys Asn Gly Ile Glu Phe Ile Asp Glu His Al #a Phe Lys Gly Val Ala             100       #           105       #           110 Glu Thr Leu Gln Thr Leu Asp Leu Ser Asp As #n Arg Ile Gln Ser Val         115           #       120           #       125 His Lys Asn Ala Phe Asn Asn Leu Lys Ala Ar #g Ala Arg Ile Ala Asn     130               #   135               #   140 Asn Pro Trp His Cys Asp Cys Thr Leu Gln Gl #n Val Leu Arg Ser Met 145                 1 #50                 1 #55                 1 #60 Ala Ser Asn His Glu Thr Ala His Asn Val Il #e Cys Lys Thr Ser Val                 165   #               170   #               175 Leu Asp Glu His Ala Gly Arg Pro Phe Leu As #n Ala Ala Asn Asp Ala             180       #           185       #           190 Asp Leu Cys Asn Leu Pro Lys Lys Thr Thr As #p Tyr Ala Met Leu Val         195           #       200           #       205 Thr Met Phe Gly Trp Phe Thr Met Val Ile Se #r Tyr Val Val Tyr Tyr     210               #   215               #   220 Val Arg Gln Asn Gln Glu Asp Ala Arg Arg Hi #s Leu Glu Tyr Leu Lys 225                 2 #30                 2 #35                 2 #40 Ser Leu Pro Ser Arg Gln Lys Lys Ala Asp Gl #u Pro Asp Asp Ile Ser                 245   #               250   #               255 Thr Val Val <210> SEQ ID NO 72 <211> LENGTH: 2290 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 accgagccga gcggaccgaa ggcgcgcccg agatgcaggt gagcaagagg at #gctggcgg     60 ggggcgtgag gagcatgccc agccccctcc tggcctgctg gcagcccatc ct #cctgctgg    120 tgctgggctc agtgctgtca ggctcggcca cgggctgccc gccccgctgc ga #gtgctccg    180 cccaggaccg cgctgtgctg tgccaccgca agtgctttgt ggcagtcccc ga #gggcatcc    240 ccaccgagac gcgcctgctg gacctaggca agaaccgcat caaaacgctc aa #ccaggacg    300 agttcgccag cttcccgcac ctggaggagc tggagctcaa cgagaacatc gt #gagcgccg    360 tggagcccgg cgccttcaac aacctcttca acctccggac gctgggtctc cg #cagcaacc    420 gcctgaagct catcccgcta ggcgtcttca ctggcctcag caacctgacc aa #gcaggaca    480 tcagcgagaa caagatcgtt atcctactgg actacatgtt tcaggacctg ta #caacctca    540 agtcactgga ggttggcgac aatgacctcg tctacatctc tcaccgcgcc tt #cagcggcc    600 tcaacagcct ggagcagctg acgctggaga aatgcaacct gacctccatc cc #caccgagg    660 cgctgtccca cctgcacggc ctcatcgtcc tgaggctccg gcacctcaac at #caatgcca    720 tccgggacta ctccttcaag aggctgtacc gactcaaggt cttggagatc tc #ccactggc    780 cctacttgga caccatgaca cccaactgcc tctacggcct caacctgacg tc #cctgtcca    840 tcacacactg caatctgacc gctgtgccct acctggccgt ccgccaccta gt #ctatctcc    900 gcttcctcaa cctctcctac aaccccatca gcaccattga gggctccatg tt #gcatgagc    960 tgctccggct gcaggagatc cagctggtgg gcgggcagct ggccgtggtg ga #gccctatg   1020 ccttccgcgg cctcaactac ctgcgcgtgc tcaatgtctc tggcaaccag ct #gaccacac   1080 tggaggaatc agtcttccac tcggtgggca acctggagac actcatcctg ga #ctccaacc   1140 cgctggcctg cgactgtcgg ctcctgtggg tgttccggcg ccgctggcgg ct #caacttca   1200 accggcagca gcccacgtgc gccacgcccg agtttgtcca gggcaaggag tt #caaggact   1260 tccctgatgt gctactgccc aactacttca cctgccgccg cgcccgcatc cg #ggaccgca   1320 aggcccagca ggtgtttgtg gacgagggcc acacggtgca gtttgtgtgc cg #ggccgatg   1380 gcgacccgcc gcccgccatc ctctggctct caccccgaaa gcacctggtc tc #agccaaga   1440 gcaatgggcg gctcacagtc ttccctgatg gcacgctgga ggtgcgctac gc #ccaggtac   1500 aggacaacgg cacgtacctg tgcatcgcgg ccaacgcggg cggcaacgac tc #catgcccg   1560 cccacctgca tgtgcgcagc tactcgcccg actggcccca tcagcccaac aa #gaccttcg   1620 ctttcatctc caaccagccg ggcgagggag aggccaacag cacccgcgcc ac #tgtgcctt   1680 tccccttcga catcaagacc ctcatcatcg ccaccaccat gggcttcatc tc #tttcctgg   1740 gcgtcgtcct cttctgcctg gtgctgctgt ttctctggag ccggggcaag gg #caacacaa   1800 agcacaacat cgagatcgag tatgtgcccc gaaagtcgga cgcaggcatc ag #ctccgccg   1860 acgcgccccg caagttcaac atgaagatga tatgaggccg gggcgggggg ca #gggacccc   1920 cgggcggccg ggcaggggaa ggggcctggt cgccacctgc tcactctcca gt #ccttccca   1980 cctcctccct acccttctac acacgttctc tttctccctc ccgcctccgt cc #cctgctgc   2040 cccccgccag ccctcaccac ctgccctcct tctaccagga cctcagaagc cc #agacctgg   2100 ggaccccacc tacacagggg cattgacaga ctggagttga aagccgacga ac #cgacacgc   2160 ggcagagtca ataattcaat aaaaaagtta cgaactttct ctgtaacttg gg #tttcaata   2220 attatggatt tttatgaaaa cttgaaataa taaaaagaga aaaaaactaa aa #aaaaaaaa   2280 aaaaaaaaaa                 #                   #                   #      2290 <210> SEQ ID NO 73 <211> LENGTH: 620 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 73 Met Gln Val Ser Lys Arg Met Leu Ala Gly Gl #y Val Arg Ser Met Pro   1               5  #                 10  #                 15 Ser Pro Leu Leu Ala Cys Trp Gln Pro Ile Le #u Leu Leu Val Leu Gly              20      #             25      #             30 Ser Val Leu Ser Gly Ser Ala Thr Gly Cys Pr #o Pro Arg Cys Glu Cys          35          #         40          #         45 Ser Ala Gln Asp Arg Ala Val Leu Cys His Ar #g Lys Cys Phe Val Ala      50              #     55              #     60 Val Pro Glu Gly Ile Pro Thr Glu Thr Arg Le #u Leu Asp Leu Gly Lys  65                  # 70                  # 75                  # 80 Asn Arg Ile Lys Thr Leu Asn Gln Asp Glu Ph #e Ala Ser Phe Pro His                  85  #                 90  #                 95 Leu Glu Glu Leu Glu Leu Asn Glu Asn Ile Va #l Ser Ala Val Glu Pro             100       #           105       #           110 Gly Ala Phe Asn Asn Leu Phe Asn Leu Arg Th #r Leu Gly Leu Arg Ser         115           #       120           #       125 Asn Arg Leu Lys Leu Ile Pro Leu Gly Val Ph #e Thr Gly Leu Ser Asn     130               #   135               #   140 Leu Thr Lys Gln Asp Ile Ser Glu Asn Lys Il #e Val Ile Leu Leu Asp 145                 1 #50                 1 #55                 1 #60 Tyr Met Phe Gln Asp Leu Tyr Asn Leu Lys Se #r Leu Glu Val Gly Asp                 165   #               170   #               175 Asn Asp Leu Val Tyr Ile Ser His Arg Ala Ph #e Ser Gly Leu Asn Ser             180       #           185       #           190 Leu Glu Gln Leu Thr Leu Glu Lys Cys Asn Le #u Thr Ser Ile Pro Thr         195           #       200           #       205 Glu Ala Leu Ser His Leu His Gly Leu Ile Va #l Leu Arg Leu Arg His     210               #   215               #   220 Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Ph #e Lys Arg Leu Tyr Arg 225                 2 #30                 2 #35                 2 #40 Leu Lys Val Leu Glu Ile Ser His Trp Pro Ty #r Leu Asp Thr Met Thr                 245   #               250   #               255 Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr Se #r Leu Ser Ile Thr His             260       #           265       #           270 Cys Asn Leu Thr Ala Val Pro Tyr Leu Ala Va #l Arg His Leu Val Tyr         275           #       280           #       285 Leu Arg Phe Leu Asn Leu Ser Tyr Asn Pro Il #e Ser Thr Ile Glu Gly     290               #   295               #   300 Ser Met Leu His Glu Leu Leu Arg Leu Gln Gl #u Ile Gln Leu Val Gly 305                 3 #10                 3 #15                 3 #20 Gly Gln Leu Ala Val Val Glu Pro Tyr Ala Ph #e Arg Gly Leu Asn Tyr                 325   #               330   #               335 Leu Arg Val Leu Asn Val Ser Gly Asn Gln Le #u Thr Thr Leu Glu Glu             340       #           345       #           350 Ser Val Phe His Ser Val Gly Asn Leu Glu Th #r Leu Ile Leu Asp Ser         355           #       360           #       365 Asn Pro Leu Ala Cys Asp Cys Arg Leu Leu Tr #p Val Phe Arg Arg Arg     370               #   375               #   380 Trp Arg Leu Asn Phe Asn Arg Gln Gln Pro Th #r Cys Ala Thr Pro Glu 385                 3 #90                 3 #95                 4 #00 Phe Val Gln Gly Lys Glu Phe Lys Asp Phe Pr #o Asp Val Leu Leu Pro                 405   #               410   #               415 Asn Tyr Phe Thr Cys Arg Arg Ala Arg Ile Ar #g Asp Arg Lys Ala Gln             420       #           425       #           430 Gln Val Phe Val Asp Glu Gly His Thr Val Gl #n Phe Val Cys Arg Ala         435           #       440           #       445 Asp Gly Asp Pro Pro Pro Ala Ile Leu Trp Le #u Ser Pro Arg Lys His     450               #   455               #   460 Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Th #r Val Phe Pro Asp Gly 465                 4 #70                 4 #75                 4 #80 Thr Leu Glu Val Arg Tyr Ala Gln Val Gln As #p Asn Gly Thr Tyr Leu                 485   #               490   #               495 Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Se #r Met Pro Ala His Leu             500       #           505       #           510 His Val Arg Ser Tyr Ser Pro Asp Trp Pro Hi #s Gln Pro Asn Lys Thr         515           #       520           #       525 Phe Ala Phe Ile Ser Asn Gln Pro Gly Glu Gl #y Glu Ala Asn Ser Thr     530               #   535               #   540 Arg Ala Thr Val Pro Phe Pro Phe Asp Ile Ly #s Thr Leu Ile Ile Ala 545                 5 #50                 5 #55                 5 #60 Thr Thr Met Gly Phe Ile Ser Phe Leu Gly Va #l Val Leu Phe Cys Leu                 565   #               570   #               575 Val Leu Leu Phe Leu Trp Ser Arg Gly Lys Gl #y Asn Thr Lys His Asn             580       #           585       #           590 Ile Glu Ile Glu Tyr Val Pro Arg Lys Ser As #p Ala Gly Ile Ser Ser         595           #       600           #       605 Ala Asp Ala Pro Arg Lys Phe Asn Met Lys Me #t Ile     610               #   615               #   620 <210> SEQ ID NO 74 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 74 tcacctggag cctttattgg cc            #                   #                 22 <210> SEQ ID NO 75 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 75 ataccagcta taaccaggct gcg            #                   #                23 <210> SEQ ID NO 76 <211> LENGTH: 52 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 76 caacagtaag tggtttgatg ctcttccaaa tctagagatt ctgatgattg   #              50 gg                   #                   #                   #              52 <210> SEQ ID NO 77 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 77 ccatgtgtct cctcctacaa ag            #                   #                 22 <210> SEQ ID NO 78 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 78 gggaatagat gtgatctgat tgg            #                   #                23 <210> SEQ ID NO 79 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 79 cacctgtagc aatgcaaatc tcaaggaaat acctagagat cttcctcctg   #              50 <210> SEQ ID NO 80 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 80 agcaaccgcc tgaagctcat cc            #                   #                 22 <210> SEQ ID NO 81 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 81 aaggcgcggt gaaagatgta gacg           #                   #                24 <210> SEQ ID NO 82 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 82 gactacatgt ttcaggacct gtacaacctc aagtcactgg aggttggcga   #              50 <210> SEQ ID NO 83 <211> LENGTH: 1685 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 cccacgcgtc cgcacctcgg ccccgggctc cgaagcggct cgggggcgcc ct #ttcggtca     60 acatcgtagt ccaccccctc cccatcccca gcccccgggg attcaggctc gc #cagcgccc    120 agccagggag ccggccggga agcgcgatgg gggccccagc cgcctcgctc ct #gctcctgc    180 tcctgctgtt cgcctgctgc tgggcgcccg gcggggccaa cctctcccag ga #cgacagcc    240 agccctggac atctgatgaa acagtggtgg ctggtggcac cgtggtgctc aa #gtgccaag    300 tgaaagatca cgaggactca tccctgcaat ggtctaaccc tgctcagcag ac #tctctact    360 ttggggagaa gagagccctt cgagataatc gaattcagct ggttacctct ac #gccccacg    420 agctcagcat cagcatcagc aatgtggccc tggcagacga gggcgagtac ac #ctgctcaa    480 tcttcactat gcctgtgcga actgccaagt ccctcgtcac tgtgctagga at #tccacaga    540 agcccatcat cactggttat aaatcttcat tacgggaaaa agacacagcc ac #cctaaact    600 gtcagtcttc tgggagcaag cctgcagccc ggctcacctg gagaaagggt ga #ccaagaac    660 tccacggaga accaacccgc atacaggaag atcccaatgg taaaaccttc ac #tgtcagca    720 gctcggtgac attccaggtt acccgggagg atgatggggc gagcatcgtg tg #ctctgtga    780 accatgaatc tctaaaggga gctgacagat ccacctctca acgcattgaa gt #tttataca    840 caccaactgc gatgattagg ccagaccctc cccatcctcg tgagggccag aa #gctgttgc    900 tacactgtga gggtcgcggc aatccagtcc cccagcagta cctatgggag aa #ggagggca    960 gtgtgccacc cctgaagatg acccaggaga gtgccctgat cttccctttc ct #caacaaga   1020 gtgacagtgg cacctacggc tgcacagcca ccagcaacat gggcagctac aa #ggcctact   1080 acaccctcaa tgttaatgac cccagtccgg tgccctcctc ctccagcacc ta #ccacgcca   1140 tcatcggtgg gatcgtggct ttcattgtct tcctgctgct catcatgctc at #cttccttg   1200 gccactactt gatccggcac aaaggaacct acctgacaca tgaggcaaaa gg #ctccgacg   1260 atgctccaga cgcggacacg gccatcatca atgcagaagg cgggcagtca gg #aggggacg   1320 acaagaagga atatttcatc tagaggcgcc tgcccacttc ctgcgccccc ca #ggggccct   1380 gtggggactg ctggggccgt caccaacccg gacttgtaca gagcaaccgc ag #ggccgccc   1440 ctcccgcttg ctccccagcc cacccacccc cctgtacaga atgtctgctt tg #ggtgcggt   1500 tttgtactcg gtttggaatg gggagggagg agggcggggg gaggggaggg tt #gccctcag   1560 ccctttccgt ggcttctctg catttgggtt attattattt ttgtaacaat cc #caaatcaa   1620 atctgtctcc aggctggaga ggcaggagcc ctggggtgag aaaagcaaaa aa #caaacaaa   1680 aaaca                  #                   #                   #          1685 <210> SEQ ID NO 84 <211> LENGTH: 398 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 Met Gly Ala Pro Ala Ala Ser Leu Leu Leu Le #u Leu Leu Leu Phe Ala   1               5  #                 10  #                 15 Cys Cys Trp Ala Pro Gly Gly Ala Asn Leu Se #r Gln Asp Asp Ser Gln              20      #             25      #             30 Pro Trp Thr Ser Asp Glu Thr Val Val Ala Gl #y Gly Thr Val Val Leu          35          #         40          #         45 Lys Cys Gln Val Lys Asp His Glu Asp Ser Se #r Leu Gln Trp Ser Asn      50              #     55              #     60 Pro Ala Gln Gln Thr Leu Tyr Phe Gly Glu Ly #s Arg Ala Leu Arg Asp  65                  # 70                  # 75                  # 80 Asn Arg Ile Gln Leu Val Thr Ser Thr Pro Hi #s Glu Leu Ser Ile Ser                  85  #                 90  #                 95 Ile Ser Asn Val Ala Leu Ala Asp Glu Gly Gl #u Tyr Thr Cys Ser Ile             100       #           105       #           110 Phe Thr Met Pro Val Arg Thr Ala Lys Ser Le #u Val Thr Val Leu Gly         115           #       120           #       125 Ile Pro Gln Lys Pro Ile Ile Thr Gly Tyr Ly #s Ser Ser Leu Arg Glu     130               #   135               #   140 Lys Asp Thr Ala Thr Leu Asn Cys Gln Ser Se #r Gly Ser Lys Pro Ala 145                 1 #50                 1 #55                 1 #60 Ala Arg Leu Thr Trp Arg Lys Gly Asp Gln Gl #u Leu His Gly Glu Pro                 165   #               170   #               175 Thr Arg Ile Gln Glu Asp Pro Asn Gly Lys Th #r Phe Thr Val Ser Ser             180       #           185       #           190 Ser Val Thr Phe Gln Val Thr Arg Glu Asp As #p Gly Ala Ser Ile Val         195           #       200           #       205 Cys Ser Val Asn His Glu Ser Leu Lys Gly Al #a Asp Arg Ser Thr Ser     210               #   215               #   220 Gln Arg Ile Glu Val Leu Tyr Thr Pro Thr Al #a Met Ile Arg Pro Asp 225                 2 #30                 2 #35                 2 #40 Pro Pro His Pro Arg Glu Gly Gln Lys Leu Le #u Leu His Cys Glu Gly                 245   #               250   #               255 Arg Gly Asn Pro Val Pro Gln Gln Tyr Leu Tr #p Glu Lys Glu Gly Ser             260       #           265       #           270 Val Pro Pro Leu Lys Met Thr Gln Glu Ser Al #a Leu Ile Phe Pro Phe         275           #       280           #       285 Leu Asn Lys Ser Asp Ser Gly Thr Tyr Gly Cy #s Thr Ala Thr Ser Asn     290               #   295               #   300 Met Gly Ser Tyr Lys Ala Tyr Tyr Thr Leu As #n Val Asn Asp Pro Ser 305                 3 #10                 3 #15                 3 #20 Pro Val Pro Ser Ser Ser Ser Thr Tyr His Al #a Ile Ile Gly Gly Ile                 325   #               330   #               335 Val Ala Phe Ile Val Phe Leu Leu Leu Ile Me #t Leu Ile Phe Leu Gly             340       #           345       #           350 His Tyr Leu Ile Arg His Lys Gly Thr Tyr Le #u Thr His Glu Ala Lys         355           #       360           #       365 Gly Ser Asp Asp Ala Pro Asp Ala Asp Thr Al #a Ile Ile Asn Ala Glu     370               #   375               #   380 Gly Gly Gln Ser Gly Gly Asp Asp Lys Lys Gl #u Tyr Phe Ile 385                 3 #90                 3 #95 <210> SEQ ID NO 85 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 85 gctaggaatt ccacagaagc cc            #                   #                 22 <210> SEQ ID NO 86 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 86 aacctggaat gtcaccgagc tg            #                   #                 22 <210> SEQ ID NO 87 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 87 cctagcacag tgacgaggga cttggc           #                   #              26 <210> SEQ ID NO 88 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 88 aagacacagc caccctaaac tgtcagtctt ctgggagcaa gcctgcagcc   #              50 <210> SEQ ID NO 89 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 89 gccctggcag acgagggcga gtacacctgc tcaatcttca ctatgcctgt   #              50 <210> SEQ ID NO 90 <211> LENGTH: 2755 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 gggggttagg gaggaaggaa tccaccccca cccccccaaa cccttttctt ct #cctttcct     60 ggcttcggac attggagcac taaatgaact tgaattgtgt ctgtggcgag ca #ggatggtc    120 gctgttactt tgtgatgaga tcggggatga attgctcgct ttaaaaatgc tg #ctttggat    180 tctgttgctg gagacgtctc tttgttttgc cgctggaaac gttacagggg ac #gtttgcaa    240 agagaagatc tgttcctgca atgagataga aggggaccta cacgtagact gt #gaaaaaaa    300 gggcttcaca agtctgcagc gtttcactgc cccgacttcc cagttttacc at #ttatttct    360 gcatggcaat tccctcactc gacttttccc taatgagttc gctaactttt at #aatgcggt    420 tagtttgcac atggaaaaca atggcttgca tgaaatcgtt ccgggggctt tt #ctggggct    480 gcagctggtg aaaaggctgc acatcaacaa caacaagatc aagtcttttc ga #aagcagac    540 ttttctgggg ctggacgatc tggaatatct ccaggctgat tttaatttat ta #cgagatat    600 agacccgggg gccttccagg acttgaacaa gctggaggtg ctcattttaa at #gacaatct    660 catcagcacc ctacctgcca acgtgttcca gtatgtgccc atcacccacc tc #gacctccg    720 gggtaacagg ctgaaaacgc tgccctatga ggaggtcttg gagcaaatcc ct #ggtattgc    780 ggagatcctg ctagaggata acccttggga ctgcacctgt gatctgctct cc #ctgaaaga    840 atggctggaa aacattccca agaatgccct gatcggccga gtggtctgcg aa #gcccccac    900 cagactgcag ggtaaagacc tcaatgaaac caccgaacag gacttgtgtc ct #ttgaaaaa    960 ccgagtggat tctagtctcc cggcgccccc tgcccaagaa gagacctttg ct #cctggacc   1020 cctgccaact cctttcaaga caaatgggca agaggatcat gccacaccag gg #tctgctcc   1080 aaacggaggt acaaagatcc caggcaactg gcagatcaaa atcagaccca ca #gcagcgat   1140 agcgacgggt agctccagga acaaaccctt agctaacagt ttaccctgcc ct #gggggctg   1200 cagctgcgac cacatcccag ggtcgggttt aaagatgaac tgcaacaaca gg #aacgtgag   1260 cagcttggct gatttgaagc ccaagctctc taacgtgcag gagcttttcc ta #cgagataa   1320 caagatccac agcatccgaa aatcgcactt tgtggattac aagaacctca tt #ctgttgga   1380 tctgggcaac aataacatcg ctactgtaga gaacaacact ttcaagaacc tt #ttggacct   1440 caggtggcta tacatggata gcaattacct ggacacgctg tcccgggaga aa #ttcgcggg   1500 gctgcaaaac ctagagtacc tgaacgtgga gtacaacgct atccagctca tc #ctcccggg   1560 cactttcaat gccatgccca aactgaggat cctcattctc aacaacaacc tg #ctgaggtc   1620 cctgcctgtg gacgtgttcg ctggggtctc gctctctaaa ctcagcctgc ac #aacaatta   1680 cttcatgtac ctcccggtgg caggggtgct ggaccagtta acctccatca tc #cagataga   1740 cctccacgga aacccctggg agtgctcctg cacaattgtg cctttcaagc ag #tgggcaga   1800 acgcttgggt tccgaagtgc tgatgagcga cctcaagtgt gagacgccgg tg #aacttctt   1860 tagaaaggat ttcatgctcc tctccaatga cgagatctgc cctcagctgt ac #gctaggat   1920 ctcgcccacg ttaacttcgc acagtaaaaa cagcactggg ttggcggaga cc #gggacgca   1980 ctccaactcc tacctagaca ccagcagggt gtccatctcg gtgttggtcc cg #ggactgct   2040 gctggtgttt gtcacctccg ccttcaccgt ggtgggcatg ctcgtgttta tc #ctgaggaa   2100 ccgaaagcgg tccaagagac gagatgccaa ctcctccgcg tccgagatta at #tccctaca   2160 gacagtctgt gactcttcct actggcacaa tgggccttac aacgcagatg gg #gcccacag   2220 agtgtatgac tgtggctctc actcgctctc agactaagac cccaacccca at #aggggagg   2280 gcagagggaa ggcgatacat ccttccccac cgcaggcacc ccgggggctg ga #ggggcgtg   2340 tacccaaatc cccgcgccat cagcctggat gggcataagt agataaataa ct #gtgagctc   2400 gcacaaccga aagggcctga ccccttactt agctccctcc ttgaaacaaa ga #gcagactg   2460 tggagagctg ggagagcgca gccagctcgc tctttgctga gagccccttt tg #acagaaag   2520 cccagcacga ccctgctgga agaactgaca gtgccctcgc cctcggcccc gg #ggcctgtg   2580 gggttggatg ccgcggttct atacatatat acatatatcc acatctatat ag #agagatag   2640 atatctattt ttcccctgtg gattagcccc gtgatggctc cctgttggct ac #gcagggat   2700 gggcagttgc acgaaggcat gaatgtattg taaataagta actttgactt ct #gac        2755 <210> SEQ ID NO 91 <211> LENGTH: 696 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 91 Met Leu Leu Trp Ile Leu Leu Leu Glu Thr Se #r Leu Cys Phe Ala Ala   1               5  #                 10  #                 15 Gly Asn Val Thr Gly Asp Val Cys Lys Glu Ly #s Ile Cys Ser Cys Asn              20      #             25      #             30 Glu Ile Glu Gly Asp Leu His Val Asp Cys Gl #u Lys Lys Gly Phe Thr          35          #         40          #         45 Ser Leu Gln Arg Phe Thr Ala Pro Thr Ser Gl #n Phe Tyr His Leu Phe      50              #     55              #     60 Leu His Gly Asn Ser Leu Thr Arg Leu Phe Pr #o Asn Glu Phe Ala Asn  65                  # 70                  # 75                  # 80 Phe Tyr Asn Ala Val Ser Leu His Met Glu As #n Asn Gly Leu His Glu                  85  #                 90  #                 95 Ile Val Pro Gly Ala Phe Leu Gly Leu Gln Le #u Val Lys Arg Leu His             100       #           105       #           110 Ile Asn Asn Asn Lys Ile Lys Ser Phe Arg Ly #s Gln Thr Phe Leu Gly         115           #       120           #       125 Leu Asp Asp Leu Glu Tyr Leu Gln Ala Asp Ph #e Asn Leu Leu Arg Asp     130               #   135               #   140 Ile Asp Pro Gly Ala Phe Gln Asp Leu Asn Ly #s Leu Glu Val Leu Ile 145                 1 #50                 1 #55                 1 #60 Leu Asn Asp Asn Leu Ile Ser Thr Leu Pro Al #a Asn Val Phe Gln Tyr                 165   #               170   #               175 Val Pro Ile Thr His Leu Asp Leu Arg Gly As #n Arg Leu Lys Thr Leu             180       #           185       #           190 Pro Tyr Glu Glu Val Leu Glu Gln Ile Pro Gl #y Ile Ala Glu Ile Leu         195           #       200           #       205 Leu Glu Asp Asn Pro Trp Asp Cys Thr Cys As #p Leu Leu Ser Leu Lys     210               #   215               #   220 Glu Trp Leu Glu Asn Ile Pro Lys Asn Ala Le #u Ile Gly Arg Val Val 225                 2 #30                 2 #35                 2 #40 Cys Glu Ala Pro Thr Arg Leu Gln Gly Lys As #p Leu Asn Glu Thr Thr                 245   #               250   #               255 Glu Gln Asp Leu Cys Pro Leu Lys Asn Arg Va #l Asp Ser Ser Leu Pro             260       #           265       #           270 Ala Pro Pro Ala Gln Glu Glu Thr Phe Ala Pr #o Gly Pro Leu Pro Thr         275           #       280           #       285 Pro Phe Lys Thr Asn Gly Gln Glu Asp His Al #a Thr Pro Gly Ser Ala     290               #   295               #   300 Pro Asn Gly Gly Thr Lys Ile Pro Gly Asn Tr #p Gln Ile Lys Ile Arg 305                 3 #10                 3 #15                 3 #20 Pro Thr Ala Ala Ile Ala Thr Gly Ser Ser Ar #g Asn Lys Pro Leu Ala                 325   #               330   #               335 Asn Ser Leu Pro Cys Pro Gly Gly Cys Ser Cy #s Asp His Ile Pro Gly             340       #           345       #           350 Ser Gly Leu Lys Met Asn Cys Asn Asn Arg As #n Val Ser Ser Leu Ala         355           #       360           #       365 Asp Leu Lys Pro Lys Leu Ser Asn Val Gln Gl #u Leu Phe Leu Arg Asp     370               #   375               #   380 Asn Lys Ile His Ser Ile Arg Lys Ser His Ph #e Val Asp Tyr Lys Asn 385                 3 #90                 3 #95                 4 #00 Leu Ile Leu Leu Asp Leu Gly Asn Asn Asn Il #e Ala Thr Val Glu Asn                 405   #               410   #               415 Asn Thr Phe Lys Asn Leu Leu Asp Leu Arg Tr #p Leu Tyr Met Asp Ser             420       #           425       #           430 Asn Tyr Leu Asp Thr Leu Ser Arg Glu Lys Ph #e Ala Gly Leu Gln Asn         435           #       440           #       445 Leu Glu Tyr Leu Asn Val Glu Tyr Asn Ala Il #e Gln Leu Ile Leu Pro     450               #   455               #   460 Gly Thr Phe Asn Ala Met Pro Lys Leu Arg Il #e Leu Ile Leu Asn Asn 465                 4 #70                 4 #75                 4 #80 Asn Leu Leu Arg Ser Leu Pro Val Asp Val Ph #e Ala Gly Val Ser Leu                 485   #               490   #               495 Ser Lys Leu Ser Leu His Asn Asn Tyr Phe Me #t Tyr Leu Pro Val Ala             500       #           505       #           510 Gly Val Leu Asp Gln Leu Thr Ser Ile Ile Gl #n Ile Asp Leu His Gly         515           #       520           #       525 Asn Pro Trp Glu Cys Ser Cys Thr Ile Val Pr #o Phe Lys Gln Trp Ala     530               #   535               #   540 Glu Arg Leu Gly Ser Glu Val Leu Met Ser As #p Leu Lys Cys Glu Thr 545                 5 #50                 5 #55                 5 #60 Pro Val Asn Phe Phe Arg Lys Asp Phe Met Le #u Leu Ser Asn Asp Glu                 565   #               570   #               575 Ile Cys Pro Gln Leu Tyr Ala Arg Ile Ser Pr #o Thr Leu Thr Ser His             580       #           585       #           590 Ser Lys Asn Ser Thr Gly Leu Ala Glu Thr Gl #y Thr His Ser Asn Ser         595           #       600           #       605 Tyr Leu Asp Thr Ser Arg Val Ser Ile Ser Va #l Leu Val Pro Gly Leu     610               #   615               #   620 Leu Leu Val Phe Val Thr Ser Ala Phe Thr Va #l Val Gly Met Leu Val 625                 6 #30                 6 #35                 6 #40 Phe Ile Leu Arg Asn Arg Lys Arg Ser Lys Ar #g Arg Asp Ala Asn Ser                 645   #               650   #               655 Ser Ala Ser Glu Ile Asn Ser Leu Gln Thr Va #l Cys Asp Ser Ser Tyr             660       #           665       #           670 Trp His Asn Gly Pro Tyr Asn Ala Asp Gly Al #a His Arg Val Tyr Asp         675           #       680           #       685 Cys Gly Ser His Ser Leu Ser Asp     690               #   695 <210> SEQ ID NO 92 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 92 gttggatctg ggcaacaata ac            #                   #                 22 <210> SEQ ID NO 93 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 93 attgttgtgc aggctgagtt taag           #                   #                24 <210> SEQ ID NO 94 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 94 ggtggctata catggatagc aattacctgg acacgctgtc ccggg    #                   #45 <210> SEQ ID NO 95 <211> LENGTH: 2226 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 95 agtcgactgc gtcccctgta cccggcgcca gctgtgttcc tgaccccaga at #aactcagg     60 gctgcaccgg gcctggcagc gctccgcaca catttcctgt cgcggcctaa gg #gaaactgt    120 tggccgctgg gcccgcgggg ggattcttgg cagttggggg gtccgtcggg ag #cgagggcg    180 gaggggaagg gagggggaac cgggttgggg aagccagctg tagagggcgg tg #accgcgct    240 ccagacacag ctctgcgtcc tcgagcggga cagatccaag ttgggagcag ct #ctgcgtgc    300 ggggcctcag agaatgaggc cggcgttcgc cctgtgcctc ctctggcagg cg #ctctggcc    360 cgggccgggc ggcggcgaac accccactgc cgaccgtgct ggctgctcgg cc #tcgggggc    420 ctgctacagc ctgcaccacg ctaccatgaa gcggcaggcg gccgaggagg cc #tgcatcct    480 gcgaggtggg gcgctcagca ccgtgcgtgc gggcgccgag ctgcgcgctg tg #ctcgcgct    540 cctgcgggca ggcccagggc ccggaggggg ctccaaagac ctgctgttct gg #gtcgcact    600 ggagcgcagg cgttcccact gcaccctgga gaacgagcct ttgcggggtt tc #tcctggct    660 gtcctccgac cccggcggtc tcgaaagcga cacgctgcag tgggtggagg ag #ccccaacg    720 ctcctgcacc gcgcggagat gcgcggtact ccaggccacc ggtggggtcg ag #cccgcagg    780 ctggaaggag atgcgatgcc acctgcgcgc caacggctac ctgtgcaagt ac #cagtttga    840 ggtcttgtgt cctgcgccgc gccccggggc cgcctctaac ttgagctatc gc #gcgccctt    900 ccagctgcac agcgccgctc tggacttcag tccacctggg accgaggtga gt #gcgctctg    960 ccggggacag ctcccgatct cagttacttg catcgcggac gaaatcggcg ct #cgctggga   1020 caaactctcg ggcgatgtgt tgtgtccctg ccccgggagg tacctccgtg ct #ggcaaatg   1080 cgcagagctc cctaactgcc tagacgactt gggaggcttt gcctgcgaat gt #gctacggg   1140 cttcgagctg gggaaggacg gccgctcttg tgtgaccagt ggggaaggac ag #ccgaccct   1200 tggggggacc ggggtgccca ccaggcgccc gccggccact gcaaccagcc cc #gtgccgca   1260 gagaacatgg ccaatcaggg tcgacgagaa gctgggagag acaccacttg tc #cctgaaca   1320 agacaattca gtaacatcta ttcctgagat tcctcgatgg ggatcacaga gc #acgatgtc   1380 tacccttcaa atgtcccttc aagccgagtc aaaggccact atcaccccat ca #gggagcgt   1440 gatttccaag tttaattcta cgacttcctc tgccactcct caggctttcg ac #tcctcctc   1500 tgccgtggtc ttcatatttg tgagcacagc agtagtagtg ttggtgatct tg #accatgac   1560 agtactgggg cttgtcaagc tctgctttca cgaaagcccc tcttcccagc ca #aggaagga   1620 gtctatgggc ccgccgggcc tggagagtga tcctgagccc gctgctttgg gc #tccagttc   1680 tgcacattgc acaaacaatg gggtgaaagt cggggactgt gatctgcggg ac #agagcaga   1740 gggtgccttg ctggcggagt cccctcttgg ctctagtgat gcatagggaa ac #aggggaca   1800 tgggcactcc tgtgaacagt ttttcacttt tgatgaaacg gggaaccaag ag #gaacttac   1860 ttgtgtaact gacaatttct gcagaaatcc cccttcctct aaattccctt ta #ctccactg   1920 aggagctaaa tcagaactgc acactccttc cctgatgata gaggaagtgg aa #gtgccttt   1980 aggatggtga tactggggga ccgggtagtg ctggggagag atattttctt at #gtttattc   2040 ggagaatttg gagaagtgat tgaacttttc aagacattgg aaacaaatag aa #cacaatat   2100 aatttacatt aaaaaataat ttctaccaaa atggaaagga aatgttctat gt #tgttcagg   2160 ctaggagtat attggttcga aatcccaggg aaaaaaataa aaataaaaaa tt #aaaggatt   2220 gttgat                  #                   #                   #         2226 <210> SEQ ID NO 96 <211> LENGTH: 490 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 Met Arg Pro Ala Phe Ala Leu Cys Leu Leu Tr #p Gln Ala Leu Trp Pro   1               5  #                 10  #                 15 Gly Pro Gly Gly Gly Glu His Pro Thr Ala As #p Arg Ala Gly Cys Ser              20      #             25      #             30 Ala Ser Gly Ala Cys Tyr Ser Leu His His Al #a Thr Met Lys Arg Gln          35          #         40          #         45 Ala Ala Glu Glu Ala Cys Ile Leu Arg Gly Gl #y Ala Leu Ser Thr Val      50              #     55              #     60 Arg Ala Gly Ala Glu Leu Arg Ala Val Leu Al #a Leu Leu Arg Ala Gly  65                  # 70                  # 75                  # 80 Pro Gly Pro Gly Gly Gly Ser Lys Asp Leu Le #u Phe Trp Val Ala Leu                  85  #                 90  #                 95 Glu Arg Arg Arg Ser His Cys Thr Leu Glu As #n Glu Pro Leu Arg Gly             100       #           105       #           110 Phe Ser Trp Leu Ser Ser Asp Pro Gly Gly Le #u Glu Ser Asp Thr Leu         115           #       120           #       125 Gln Trp Val Glu Glu Pro Gln Arg Ser Cys Th #r Ala Arg Arg Cys Ala     130               #   135               #   140 Val Leu Gln Ala Thr Gly Gly Val Glu Pro Al #a Gly Trp Lys Glu Met 145                 1 #50                 1 #55                 1 #60 Arg Cys His Leu Arg Ala Asn Gly Tyr Leu Cy #s Lys Tyr Gln Phe Glu                 165   #               170   #               175 Val Leu Cys Pro Ala Pro Arg Pro Gly Ala Al #a Ser Asn Leu Ser Tyr             180       #           185       #           190 Arg Ala Pro Phe Gln Leu His Ser Ala Ala Le #u Asp Phe Ser Pro Pro         195           #       200           #       205 Gly Thr Glu Val Ser Ala Leu Cys Arg Gly Gl #n Leu Pro Ile Ser Val     210               #   215               #   220 Thr Cys Ile Ala Asp Glu Ile Gly Ala Arg Tr #p Asp Lys Leu Ser Gly 225                 2 #30                 2 #35                 2 #40 Asp Val Leu Cys Pro Cys Pro Gly Arg Tyr Le #u Arg Ala Gly Lys Cys                 245   #               250   #               255 Ala Glu Leu Pro Asn Cys Leu Asp Asp Leu Gl #y Gly Phe Ala Cys Glu             260       #           265       #           270 Cys Ala Thr Gly Phe Glu Leu Gly Lys Asp Gl #y Arg Ser Cys Val Thr         275           #       280           #       285 Ser Gly Glu Gly Gln Pro Thr Leu Gly Gly Th #r Gly Val Pro Thr Arg     290               #   295               #   300 Arg Pro Pro Ala Thr Ala Thr Ser Pro Val Pr #o Gln Arg Thr Trp Pro 305                 3 #10                 3 #15                 3 #20 Ile Arg Val Asp Glu Lys Leu Gly Glu Thr Pr #o Leu Val Pro Glu Gln                 325   #               330   #               335 Asp Asn Ser Val Thr Ser Ile Pro Glu Ile Pr #o Arg Trp Gly Ser Gln             340       #           345       #           350 Ser Thr Met Ser Thr Leu Gln Met Ser Leu Gl #n Ala Glu Ser Lys Ala         355           #       360           #       365 Thr Ile Thr Pro Ser Gly Ser Val Ile Ser Ly #s Phe Asn Ser Thr Thr     370               #   375               #   380 Ser Ser Ala Thr Pro Gln Ala Phe Asp Ser Se #r Ser Ala Val Val Phe 385                 3 #90                 3 #95                 4 #00 Ile Phe Val Ser Thr Ala Val Val Val Leu Va #l Ile Leu Thr Met Thr                 405   #               410   #               415 Val Leu Gly Leu Val Lys Leu Cys Phe His Gl #u Ser Pro Ser Ser Gln             420       #           425       #           430 Pro Arg Lys Glu Ser Met Gly Pro Pro Gly Le #u Glu Ser Asp Pro Glu         435           #       440           #       445 Pro Ala Ala Leu Gly Ser Ser Ser Ala His Cy #s Thr Asn Asn Gly Val     450               #   455               #   460 Lys Val Gly Asp Cys Asp Leu Arg Asp Arg Al #a Glu Gly Ala Leu Leu 465                 4 #70                 4 #75                 4 #80 Ala Glu Ser Pro Leu Gly Ser Ser Asp Ala                 485   #               490 <210> SEQ ID NO 97 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 97 tggaaggaga tgcgatgcca cctg           #                   #                24 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 98 tgaccagtgg ggaaggacag             #                   #                   # 20 <210> SEQ ID NO 99 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 99 acagagcaga gggtgccttg             #                   #                   # 20 <210> SEQ ID NO 100 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 100 tcagggacaa gtggtgtctc tccc           #                   #                24 <210> SEQ ID NO 101 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 101 tcagggaagg agtgtgcagt tctg           #                   #                24 <210> SEQ ID NO 102 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 102 acagctcccg atctcagtta cttgcatcgc ggacgaaatc ggcgctcgct   #              50 <210> SEQ ID NO 103 <211> LENGTH: 2026 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 103 cggacgcgtg ggattcagca gtggcctgtg gctgccagag cagctcctca gg #ggaaacta     60 agcgtcgagt cagacggcac cataatcgcc tttaaaagtg cctccgccct gc #cggccgcg    120 tatcccccgg ctacctgggc cgccccgcgg cggtgcgcgc gtgagaggga gc #gcgcgggc    180 agccgagcgc cggtgtgagc cagcgctgct gccagtgtga gcggcggtgt ga #gcgcggtg    240 ggtgcggagg ggcgtgtgtg ccggcgcgcg cgccgtgggg tgcaaacccc ga #gcgtctac    300 gctgccatga ggggcgcgaa cgcctgggcg ccactctgcc tgctgctggc tg #ccgccacc    360 cagctctcgc ggcagcagtc cccagagaga cctgttttca catgtggtgg ca #ttcttact    420 ggagagtctg gatttattgg cagtgaaggt tttcctggag tgtaccctcc aa #atagcaaa    480 tgtacttgga aaatcacagt tcccgaagga aaagtagtcg ttctcaattt cc #gattcata    540 gacctcgaga gtgacaacct gtgccgctat gactttgtgg atgtgtacaa tg #gccatgcc    600 aatggccagc gcattggccg cttctgtggc actttccggc ctggagccct tg #tgtccagt    660 ggcaacaaga tgatggtgca gatgatttct gatgccaaca cagctggcaa tg #gcttcatg    720 gccatgttct ccgctgctga accaaacgaa agaggggatc agtattgtgg ag #gactcctt    780 gacagacctt ccggctcttt taaaaccccc aactggccag accgggatta cc #ctgcagga    840 gtcacttgtg tgtggcacat tgtagcccca aagaatcagc ttatagaatt aa #agtttgag    900 aagtttgatg tggagcgaga taactactgc cgatatgatt atgtggctgt gt #ttaatggc    960 ggggaagtca acgatgctag aagaattgga aagtattgtg gtgatagtcc ac #ctgcgcca   1020 attgtgtctg agagaaatga acttcttatt cagtttttat cagacttaag tt #taactgca   1080 gatgggttta ttggtcacta catattcagg ccaaaaaaac tgcctacaac ta #cagaacag   1140 cctgtcacca ccacattccc tgtaaccacg ggtttaaaac ccaccgtggc ct #tgtgtcaa   1200 caaaagtgta gacggacggg gactctggag ggcaattatt gttcaagtga ct #ttgtatta   1260 gccggcactg ttatcacaac catcactcgc gatgggagtt tgcacgccac ag #tctcgatc   1320 atcaacatct acaaagaggg aaatttggcg attcagcagg cgggcaagaa ca #tgagtgcc   1380 aggctgactg tcgtctgcaa gcagtgccct ctcctcagaa gaggtctaaa tt #acattatt   1440 atgggccaag taggtgaaga tgggcgaggc aaaatcatgc caaacagctt ta #tcatgatg   1500 ttcaagacca agaatcagaa gctcctggat gccttaaaaa ataagcaatg tt #aacagtga   1560 actgtgtcca tttaagctgt attctgccat tgcctttgaa agatctatgt tc #tctcagta   1620 gaaaaaaaaa tacttataaa attacatatt ctgaaagagg attccgaaag at #gggactgg   1680 ttgactcttc acatgatgga ggtatgaggc ctccgagata gctgagggaa gt #tctttgcc   1740 tgctgtcaga ggagcagcta tctgattgga aacctgccga cttagtgcgg tg #ataggaag   1800 ctaaaagtgt caagcgttga cagcttggaa gcgtttattt atacatctct gt #aaaaggat   1860 attttagaat tgagttgtgt gaagatgtca aaaaaagatt ttagaagtgc aa #tatttata   1920 gtgttatttg tttcaccttc aagcctttgc cctgaggtgt tacaatcttg tc #ttgcgttt   1980 tctaaatcaa tgcttaataa aatattttta aaggaaaaaa aaaaaa    #               2026 <210> SEQ ID NO 104 <211> LENGTH: 415 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 Met Arg Gly Ala Asn Ala Trp Ala Pro Leu Cy #s Leu Leu Leu Ala Ala   1               5  #                 10  #                 15 Ala Thr Gln Leu Ser Arg Gln Gln Ser Pro Gl #u Arg Pro Val Phe Thr              20      #             25      #             30 Cys Gly Gly Ile Leu Thr Gly Glu Ser Gly Ph #e Ile Gly Ser Glu Gly          35          #         40          #         45 Phe Pro Gly Val Tyr Pro Pro Asn Ser Lys Cy #s Thr Trp Lys Ile Thr      50              #     55              #     60 Val Pro Glu Gly Lys Val Val Val Leu Asn Ph #e Arg Phe Ile Asp Leu  65                  # 70                  # 75                  # 80 Glu Ser Asp Asn Leu Cys Arg Tyr Asp Phe Va #l Asp Val Tyr Asn Gly                  85  #                 90  #                 95 His Ala Asn Gly Gln Arg Ile Gly Arg Phe Cy #s Gly Thr Phe Arg Pro             100       #           105       #           110 Gly Ala Leu Val Ser Ser Gly Asn Lys Met Me #t Val Gln Met Ile Ser         115           #       120           #       125 Asp Ala Asn Thr Ala Gly Asn Gly Phe Met Al #a Met Phe Ser Ala Ala     130               #   135               #   140 Glu Pro Asn Glu Arg Gly Asp Gln Tyr Cys Gl #y Gly Leu Leu Asp Arg 145                 1 #50                 1 #55                 1 #60 Pro Ser Gly Ser Phe Lys Thr Pro Asn Trp Pr #o Asp Arg Asp Tyr Pro                 165   #               170   #               175 Ala Gly Val Thr Cys Val Trp His Ile Val Al #a Pro Lys Asn Gln Leu             180       #           185       #           190 Ile Glu Leu Lys Phe Glu Lys Phe Asp Val Gl #u Arg Asp Asn Tyr Cys         195           #       200           #       205 Arg Tyr Asp Tyr Val Ala Val Phe Asn Gly Gl #y Glu Val Asn Asp Ala     210               #   215               #   220 Arg Arg Ile Gly Lys Tyr Cys Gly Asp Ser Pr #o Pro Ala Pro Ile Val 225                 2 #30                 2 #35                 2 #40 Ser Glu Arg Asn Glu Leu Leu Ile Gln Phe Le #u Ser Asp Leu Ser Leu                 245   #               250   #               255 Thr Ala Asp Gly Phe Ile Gly His Tyr Ile Ph #e Arg Pro Lys Lys Leu             260       #           265       #           270 Pro Thr Thr Thr Glu Gln Pro Val Thr Thr Th #r Phe Pro Val Thr Thr         275           #       280           #       285 Gly Leu Lys Pro Thr Val Ala Leu Cys Gln Gl #n Lys Cys Arg Arg Thr     290               #   295               #   300 Gly Thr Leu Glu Gly Asn Tyr Cys Ser Ser As #p Phe Val Leu Ala Gly 305                 3 #10                 3 #15                 3 #20 Thr Val Ile Thr Thr Ile Thr Arg Asp Gly Se #r Leu His Ala Thr Val                 325   #               330   #               335 Ser Ile Ile Asn Ile Tyr Lys Glu Gly Asn Le #u Ala Ile Gln Gln Ala             340       #           345       #           350 Gly Lys Asn Met Ser Ala Arg Leu Thr Val Va #l Cys Lys Gln Cys Pro         355           #       360           #       365 Leu Leu Arg Arg Gly Leu Asn Tyr Ile Ile Me #t Gly Gln Val Gly Glu     370               #   375               #   380 Asp Gly Arg Gly Lys Ile Met Pro Asn Ser Ph #e Ile Met Met Phe Lys 385                 3 #90                 3 #95                 4 #00 Thr Lys Asn Gln Lys Leu Leu Asp Ala Leu Ly #s Asn Lys Gln Cys                 405   #               410   #               415 <210> SEQ ID NO 105 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 105 ccgattcata gacctcgaga gt            #                   #                 22 <210> SEQ ID NO 106 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 106 gtcaaggagt cctccacaat ac            #                   #                 22 <210> SEQ ID NO 107 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 107 gtgtacaatg gccatgccaa tggccagcgc attggccgct tctgt    #                   #45 <210> SEQ ID NO 108 <211> LENGTH: 1838 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108 cggacgcgtg ggcggacgcg tgggcggccc acggcgcccg cgggctgggg cg #gtcgcttc     60 ttccttctcc gtggcctacg agggtcccca gcctgggtaa agatggcccc at #ggcccccg    120 aagggcctag tcccagctgt gctctggggc ctcagcctct tcctcaacct cc #caggacct    180 atctggctcc agccctctcc acctccccag tcttctcccc cgcctcagcc cc #atccgtgt    240 catacctgcc ggggactggt tgacagcttt aacaagggcc tggagagaac ca #tccgggac    300 aactttggag gtggaaacac tgcctgggag gaagagaatt tgtccaaata ca #aagacagt    360 gagacccgcc tggtagaggt gctggagggt gtgtgcagca agtcagactt cg #agtgccac    420 cgcctgctgg agctgagtga ggagctggtg gagagctggt ggtttcacaa gc #agcaggag    480 gccccggacc tcttccagtg gctgtgctca gattccctga agctctgctg cc #ccgcaggc    540 accttcgggc cctcctgcct tccctgtcct gggggaacag agaggccctg cg #gtggctac    600 gggcagtgtg aaggagaagg gacacgaggg ggcagcgggc actgtgactg cc #aagccggc    660 tacgggggtg aggcctgtgg ccagtgtggc cttggctact ttgaggcaga ac #gcaacgcc    720 agccatctgg tatgttcggc ttgttttggc ccctgtgccc gatgctcagg ac #ctgaggaa    780 tcaaactgtt tgcaatgcaa gaagggctgg gccctgcatc acctcaagtg tg #tagacatt    840 gatgagtgtg gcacagaggg agccaactgt ggagctgacc aattctgcgt ga #acactgag    900 ggctcctatg agtgccgaga ctgtgccaag gcctgcctag gctgcatggg gg #cagggcca    960 ggtcgctgta agaagtgtag ccctggctat cagcaggtgg gctccaagtg tc #tcgatgtg   1020 gatgagtgtg agacagaggt gtgtccggga gagaacaagc agtgtgaaaa ca #ccgagggc   1080 ggttatcgct gcatctgtgc cgagggctac aagcagatgg aaggcatctg tg #tgaaggag   1140 cagatcccag agtcagcagg cttcttctca gagatgacag aagacgagtt gg #tggtgctg   1200 cagcagatgt tctttggcat catcatctgt gcactggcca cgctggctgc ta #agggcgac   1260 ttggtgttca ccgccatctt cattggggct gtggcggcca tgactggcta ct #ggttgtca   1320 gagcgcagtg accgtgtgct ggagggcttc atcaagggca gataatcgcg gc #caccacct   1380 gtaggacctc ctcccaccca cgctgccccc agagcttggg ctgccctcct gc #tggacact   1440 caggacagct tggtttattt ttgagagtgg ggtaagcacc cctacctgcc tt #acagagca   1500 gcccaggtac ccaggcccgg gcagacaagg cccctggggt aaaaagtagc cc #tgaaggtg   1560 gataccatga gctcttcacc tggcggggac tggcaggctt cacaatgtgt ga #atttcaaa   1620 agtttttcct taatggtggc tgctagagct ttggcccctg cttaggatta gg #tggtcctc   1680 acaggggtgg ggccatcaca gctccctcct gccagctgca tgctgccagt tc #ctgttctg   1740 tgttcaccac atccccacac cccattgcca cttatttatt catctcagga aa #taaagaaa   1800 ggtcttggaa agttaaaaaa aaaaaaaaaa aaaaaaaa       #                   #   1838 <210> SEQ ID NO 109 <211> LENGTH: 420 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 109 Met Ala Pro Trp Pro Pro Lys Gly Leu Val Pr #o Ala Val Leu Trp Gly   1               5  #                 10  #                 15 Leu Ser Leu Phe Leu Asn Leu Pro Gly Pro Il #e Trp Leu Gln Pro Ser              20      #             25      #             30 Pro Pro Pro Gln Ser Ser Pro Pro Pro Gln Pr #o His Pro Cys His Thr          35          #         40          #         45 Cys Arg Gly Leu Val Asp Ser Phe Asn Lys Gl #y Leu Glu Arg Thr Ile      50              #     55              #     60 Arg Asp Asn Phe Gly Gly Gly Asn Thr Ala Tr #p Glu Glu Glu Asn Leu  65                  # 70                  # 75                  # 80 Ser Lys Tyr Lys Asp Ser Glu Thr Arg Leu Va #l Glu Val Leu Glu Gly                  85  #                 90  #                 95 Val Cys Ser Lys Ser Asp Phe Glu Cys His Ar #g Leu Leu Glu Leu Ser             100       #           105       #           110 Glu Glu Leu Val Glu Ser Trp Trp Phe His Ly #s Gln Gln Glu Ala Pro         115           #       120           #       125 Asp Leu Phe Gln Trp Leu Cys Ser Asp Ser Le #u Lys Leu Cys Cys Pro     130               #   135               #   140 Ala Gly Thr Phe Gly Pro Ser Cys Leu Pro Cy #s Pro Gly Gly Thr Glu 145                 1 #50                 1 #55                 1 #60 Arg Pro Cys Gly Gly Tyr Gly Gln Cys Glu Gl #y Glu Gly Thr Arg Gly                 165   #               170   #               175 Gly Ser Gly His Cys Asp Cys Gln Ala Gly Ty #r Gly Gly Glu Ala Cys             180       #           185       #           190 Gly Gln Cys Gly Leu Gly Tyr Phe Glu Ala Gl #u Arg Asn Ala Ser His         195           #       200           #       205 Leu Val Cys Ser Ala Cys Phe Gly Pro Cys Al #a Arg Cys Ser Gly Pro     210               #   215               #   220 Glu Glu Ser Asn Cys Leu Gln Cys Lys Lys Gl #y Trp Ala Leu His His 225                 2 #30                 2 #35                 2 #40 Leu Lys Cys Val Asp Ile Asp Glu Cys Gly Th #r Glu Gly Ala Asn Cys                 245   #               250   #               255 Gly Ala Asp Gln Phe Cys Val Asn Thr Glu Gl #y Ser Tyr Glu Cys Arg             260       #           265       #           270 Asp Cys Ala Lys Ala Cys Leu Gly Cys Met Gl #y Ala Gly Pro Gly Arg         275           #       280           #       285 Cys Lys Lys Cys Ser Pro Gly Tyr Gln Gln Va #l Gly Ser Lys Cys Leu     290               #   295               #   300 Asp Val Asp Glu Cys Glu Thr Glu Val Cys Pr #o Gly Glu Asn Lys Gln 305                 3 #10                 3 #15                 3 #20 Cys Glu Asn Thr Glu Gly Gly Tyr Arg Cys Il #e Cys Ala Glu Gly Tyr                 325   #               330   #               335 Lys Gln Met Glu Gly Ile Cys Val Lys Glu Gl #n Ile Pro Glu Ser Ala             340       #           345       #           350 Gly Phe Phe Ser Glu Met Thr Glu Asp Glu Le #u Val Val Leu Gln Gln         355           #       360           #       365 Met Phe Phe Gly Ile Ile Ile Cys Ala Leu Al #a Thr Leu Ala Ala Lys     370               #   375               #   380 Gly Asp Leu Val Phe Thr Ala Ile Phe Ile Gl #y Ala Val Ala Ala Met 385                 3 #90                 3 #95                 4 #00 Thr Gly Tyr Trp Leu Ser Glu Arg Ser Asp Ar #g Val Leu Glu Gly Phe                 405   #               410   #               415 Ile Lys Gly Arg             420 <210> SEQ ID NO 110 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 110 cctggctatc agcaggtggg ctccaagtgt ctcgatgtgg atgagtgtga   #              50 <210> SEQ ID NO 111 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 111 attctgcgtg aacactgagg gc            #                   #                 22 <210> SEQ ID NO 112 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 112 atctgcttgt agccctcggc ac            #                   #                 22 <210> SEQ ID NO 113 <211> LENGTH: 1616 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (1461) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 113 tgagaccctc ctgcagcctt ctcaagggac agccccactc tgcctcttgc tc #ctccaggg     60 cagcaccatg cagcccctgt ggctctgctg ggcactctgg gtgttgcccc tg #gccagccc    120 cggggccgcc ctgaccgggg agcagctcct gggcagcctg ctgcggcagc tg #cagctcaa    180 agaggtgccc accctggaca gggccgacat ggaggagctg gtcatcccca cc #cacgtgag    240 ggcccagtac gtggccctgc tgcagcgcag ccacggggac cgctcccgcg ga #aagaggtt    300 cagccagagc ttccgagagg tggccggcag gttcctggcg ttggaggcca gc #acacacct    360 gctggtgttc ggcatggagc agcggctgcc gcccaacagc gagctggtgc ag #gccgtgct    420 gcggctcttc caggagccgg tccccaaggc cgcgctgcac aggcacgggc gg #ctgtcccc    480 gcgcagcgcc cgggcccggg tgaccgtcga gtggctgcgc gtccgcgacg ac #ggctccaa    540 ccgcacctcc ctcatcgact ccaggctggt gtccgtccac gagagcggct gg #aaggcctt    600 cgacgtgacc gaggccgtga acttctggca gcagctgagc cggccccggc ag #ccgctgct    660 gctacaggtg tcggtgcaga gggagcatct gggcccgctg gcgtccggcg cc #cacaagct    720 ggtccgcttt gcctcgcagg gggcgccagc cgggcttggg gagccccagc tg #gagctgca    780 caccctggac cttggggact atggagctca gggcgactgt gaccctgaag ca #ccaatgac    840 cgagggcacc cgctgctgcc gccaggagat gtacattgac ctgcagggga tg #aagtgggc    900 cgagaactgg gtgctggagc ccccgggctt cctggcttat gagtgtgtgg gc #acctgccg    960 gcagcccccg gaggccctgg ccttcaagtg gccgtttctg gggcctcgac ag #tgcatcgc   1020 ctcggagact gactcgctgc ccatgatcgt cagcatcaag gagggaggca gg #accaggcc   1080 ccaggtggtc agcctgccca acatgagggt gcagaagtgc agctgtgcct cg #gatggtgc   1140 gctcgtgcca aggaggctcc agccataggc gcctagtgta gccatcgagg ga #cttgactt   1200 gtgtgtgttt ctgaagtgtt cgagggtacc aggagagctg gcgatgactg aa #ctgctgat   1260 ggacaaatgc tctgtgctct ctagtgagcc ctgaatttgc ttcctctgac aa #gttacctc   1320 acctaatttt tgcttctcag gaatgagaat ctttggccac tggagagccc tt #gctcagtt   1380 ttctctattc ttattattca ctgcactata ttctaagcac ttacatgtgg ag #atactgta   1440 acctgagggc agaaagccca ntgtgtcatt gtttacttgt cctgtcactg ga #tctgggct   1500 aaagtcctcc accaccactc tggacctaag acctggggtt aagtgtgggt tg #tgcatccc   1560 caatccagat aataaagact ttgtaaaaca tgaataaaac acattttatt ct #aaaa       1616 <210> SEQ ID NO 114 <211> LENGTH: 366 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 114 Met Gln Pro Leu Trp Leu Cys Trp Ala Leu Tr #p Val Leu Pro Leu Ala   1               5  #                 10  #                 15 Ser Pro Gly Ala Ala Leu Thr Gly Glu Gln Le #u Leu Gly Ser Leu Leu              20      #             25      #             30 Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Le #u Asp Arg Ala Asp Met          35          #         40          #         45 Glu Glu Leu Val Ile Pro Thr His Val Arg Al #a Gln Tyr Val Ala Leu      50              #     55              #     60 Leu Gln Arg Ser His Gly Asp Arg Ser Arg Gl #y Lys Arg Phe Ser Gln  65                  # 70                  # 75                  # 80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Al #a Leu Glu Ala Ser Thr                  85  #                 90  #                 95 His Leu Leu Val Phe Gly Met Glu Gln Arg Le #u Pro Pro Asn Ser Glu             100       #           105       #           110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Gl #u Pro Val Pro Lys Ala         115           #       120           #       125 Ala Leu His Arg His Gly Arg Leu Ser Pro Ar #g Ser Ala Arg Ala Arg     130               #   135               #   140 Val Thr Val Glu Trp Leu Arg Val Arg Asp As #p Gly Ser Asn Arg Thr 145                 1 #50                 1 #55                 1 #60 Ser Leu Ile Asp Ser Arg Leu Val Ser Val Hi #s Glu Ser Gly Trp Lys                 165   #               170   #               175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Tr #p Gln Gln Leu Ser Arg             180       #           185       #           190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Va #l Gln Arg Glu His Leu         195           #       200           #       205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Va #l Arg Phe Ala Ser Gln     210               #   215               #   220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Le #u Glu Leu His Thr Leu 225                 2 #30                 2 #35                 2 #40 Asp Leu Gly Asp Tyr Gly Ala Gln Gly Asp Cy #s Asp Pro Glu Ala Pro                 245   #               250   #               255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Gl #u Met Tyr Ile Asp Leu             260       #           265       #           270 Gln Gly Met Lys Trp Ala Glu Asn Trp Val Le #u Glu Pro Pro Gly Phe         275           #       280           #       285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Arg Gl #n Pro Pro Glu Ala Leu     290               #   295               #   300 Ala Phe Lys Trp Pro Phe Leu Gly Pro Arg Gl #n Cys Ile Ala Ser Glu 305                 3 #10                 3 #15                 3 #20 Thr Asp Ser Leu Pro Met Ile Val Ser Ile Ly #s Glu Gly Gly Arg Thr                 325   #               330   #               335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Ar #g Val Gln Lys Cys Ser             340       #           345       #           350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Ar #g Leu Gln Pro         355           #       360           #       365 <210> SEQ ID NO 115 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 115 aggactgcca taacttgcct g            #                   #                   #21 <210> SEQ ID NO 116 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 116 ataggagttg aagcagcgct gc            #                   #                 22 <210> SEQ ID NO 117 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 117 tgtgtggaca tagacgagtg ccgctaccgc tactgccagc accgc    #                   #45 <210> SEQ ID NO 118 <211> LENGTH: 1857 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 118 gtctgttccc aggagtcctt cggcggctgt tgtgtcagtg gcctgatcgc ga #tggggaca     60 aaggcgcaag tcgagaggaa actgttgtgc ctcttcatat tggcgatcct gt #tgtgctcc    120 ctggcattgg gcagtgttac agtgcactct tctgaacctg aagtcagaat tc #ctgagaat    180 aatcctgtga agttgtcctg tgcctactcg ggcttttctt ctccccgtgt gg #agtggaag    240 tttgaccaag gagacaccac cagactcgtt tgctataata acaagatcac ag #cttcctat    300 gaggaccggg tgaccttctt gccaactggt atcaccttca agtccgtgac ac #gggaagac    360 actgggacat acacttgtat ggtctctgag gaaggcggca acagctatgg gg #aggtcaag    420 gtcaagctca tcgtgcttgt gcctccatcc aagcctacag ttaacatccc ct #cctctgcc    480 accattggga accgggcagt gctgacatgc tcagaacaag atggttcccc ac #cttctgaa    540 tacacctggt tcaaagatgg gatagtgatg cctacgaatc ccaaaagcac cc #gtgccttc    600 agcaactctt cctatgtcct gaatcccaca acaggagagc tggtctttga tc #ccctgtca    660 gcctctgata ctggagaata cagctgtgag gcacggaatg ggtatgggac ac #ccatgact    720 tcaaatgctg tgcgcatgga agctgtggag cggaatgtgg gggtcatcgt gg #cagccgtc    780 cttgtaaccc tgattctcct gggaatcttg gtttttggca tctggtttgc ct #atagccga    840 ggccactttg acagaacaaa gaaagggact tcgagtaaga aggtgattta ca #gccagcct    900 agtgcccgaa gtgaaggaga attcaaacag acctcgtcat tcctggtgtg ag #cctggtcg    960 gctcaccgcc tatcatctgc atttgcctta ctcaggtgct accggactct gg #cccctgat   1020 gtctgtagtt tcacaggatg ccttatttgt cttctacacc ccacagggcc cc #ctacttct   1080 tcggatgtgt ttttaataat gtcagctatg tgccccatcc tccttcatgc cc #tccctccc   1140 tttcctacca ctgctgagtg gcctggaact tgtttaaagt gtttattccc ca #tttctttg   1200 agggatcagg aaggaatcct gggtatgcca ttgacttccc ttctaagtag ac #agcaaaaa   1260 tggcgggggt cgcaggaatc tgcactcaac tgcccacctg gctggcaggg at #ctttgaat   1320 aggtatcttg agcttggttc tgggctcttt ccttgtgtac tgacgaccag gg #ccagctgt   1380 tctagagcgg gaattagagg ctagagcggc tgaaatggtt gtttggtgat ga #cactgggg   1440 tccttccatc tctggggccc actctcttct gtcttcccat gggaagtgcc ac #tgggatcc   1500 ctctgccctg tcctcctgaa tacaagctga ctgacattga ctgtgtctgt gg #aaaatggg   1560 agctcttgtt gtggagagca tagtaaattt tcagagaact tgaagccaaa ag #gatttaaa   1620 accgctgctc taaagaaaag aaaactggag gctgggcgca gtggctcacg cc #tgtaatcc   1680 cagaggctga ggcaggcgga tcacctgagg tcgggagttc gggatcagcc tg #accaacat   1740 ggagaaaccc tactggaaat acaaagttag ccaggcatgg tggtgcatgc ct #gtagtccc   1800 agctgctcag gagcctggca acaagagcaa aactccagct caaaaaaaaa aa #aaaaa      1857 <210> SEQ ID NO 119 <211> LENGTH: 299 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 119 Met Gly Thr Lys Ala Gln Val Glu Arg Lys Le #u Leu Cys Leu Phe Ile   1               5  #                 10  #                 15 Leu Ala Ile Leu Leu Cys Ser Leu Ala Leu Gl #y Ser Val Thr Val His              20      #             25      #             30 Ser Ser Glu Pro Glu Val Arg Ile Pro Glu As #n Asn Pro Val Lys Leu          35          #         40          #         45 Ser Cys Ala Tyr Ser Gly Phe Ser Ser Pro Ar #g Val Glu Trp Lys Phe      50              #     55              #     60 Asp Gln Gly Asp Thr Thr Arg Leu Val Cys Ty #r Asn Asn Lys Ile Thr  65                  # 70                  # 75                  # 80 Ala Ser Tyr Glu Asp Arg Val Thr Phe Leu Pr #o Thr Gly Ile Thr Phe                  85  #                 90  #                 95 Lys Ser Val Thr Arg Glu Asp Thr Gly Thr Ty #r Thr Cys Met Val Ser             100       #           105       #           110 Glu Glu Gly Gly Asn Ser Tyr Gly Glu Val Ly #s Val Lys Leu Ile Val         115           #       120           #       125 Leu Val Pro Pro Ser Lys Pro Thr Val Asn Il #e Pro Ser Ser Ala Thr     130               #   135               #   140 Ile Gly Asn Arg Ala Val Leu Thr Cys Ser Gl #u Gln Asp Gly Ser Pro 145                 1 #50                 1 #55                 1 #60 Pro Ser Glu Tyr Thr Trp Phe Lys Asp Gly Il #e Val Met Pro Thr Asn                 165   #               170   #               175 Pro Lys Ser Thr Arg Ala Phe Ser Asn Ser Se #r Tyr Val Leu Asn Pro             180       #           185       #           190 Thr Thr Gly Glu Leu Val Phe Asp Pro Leu Se #r Ala Ser Asp Thr Gly         195           #       200           #       205 Glu Tyr Ser Cys Glu Ala Arg Asn Gly Tyr Gl #y Thr Pro Met Thr Ser     210               #   215               #   220 Asn Ala Val Arg Met Glu Ala Val Glu Arg As #n Val Gly Val Ile Val 225                 2 #30                 2 #35                 2 #40 Ala Ala Val Leu Val Thr Leu Ile Leu Leu Gl #y Ile Leu Val Phe Gly                 245   #               250   #               255 Ile Trp Phe Ala Tyr Ser Arg Gly His Phe As #p Arg Thr Lys Lys Gly             260       #           265       #           270 Thr Ser Ser Lys Lys Val Ile Tyr Ser Gln Pr #o Ser Ala Arg Ser Glu         275           #       280           #       285 Gly Glu Phe Lys Gln Thr Ser Ser Phe Leu Va #l     290               #   295 <210> SEQ ID NO 120 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 120 tcgcggagct gtgttctgtt tccc           #                   #                24 <210> SEQ ID NO 121 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 121 tgatcgcgat ggggacaaag gcgcaagctc gagaggaaac tgttgtgcct   #              50 <210> SEQ ID NO 122 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 122 acacctggtt caaagatggg             #                   #                   # 20 <210> SEQ ID NO 123 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 123 taggaagagt tgctgaaggc acgg           #                   #                24 <210> SEQ ID NO 124 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 124 ttgccttact caggtgctac             #                   #                   # 20 <210> SEQ ID NO 125 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 125 actcagcagt ggtaggaaag             #                   #                   # 20 <210> SEQ ID NO 126 <211> LENGTH: 1210 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 126 cagcgcgtgg ccggcgccgc tgtggggaca gcatgagcgg cggttggatg gc #gcaggttg     60 gagcgtggcg aacaggggct ctgggcctgg cgctgctgct gctgctcggc ct #cggactag    120 gcctggaggc cgccgcgagc ccgctttcca ccccgacctc tgcccaggcc gc #aggcccca    180 gctcaggctc gtgcccaccc accaagttcc agtgccgcac cagtggctta tg #cgtgcccc    240 tcacctggcg ctgcgacagg gacttggact gcagcgatgg cagcgatgag ga #ggagtgca    300 ggattgagcc atgtacccag aaagggcaat gcccaccgcc ccctggcctc cc #ctgcccct    360 gcaccggcgt cagtgactgc tctgggggaa ctgacaagaa actgcgcaac tg #cagccgcc    420 tggcctgcct agcaggcgag ctccgttgca cgctgagcga tgactgcatt cc #actcacgt    480 ggcgctgcga cggccaccca gactgtcccg actccagcga cgagctcggc tg #tggaacca    540 atgagatcct cccggaaggg gatgccacaa ccatggggcc ccctgtgacc ct #ggagagtg    600 tcacctctct caggaatgcc acaaccatgg ggccccctgt gaccctggag ag #tgtcccct    660 ctgtcgggaa tgccacatcc tcctctgccg gagaccagtc tggaagccca ac #tgcctatg    720 gggttattgc agctgctgcg gtgctcagtg caagcctggt caccgccacc ct #cctccttt    780 tgtcctggct ccgagcccag gagcgcctcc gcccactggg gttactggtg gc #catgaagg    840 agtccctgct gctgtcagaa cagaagacct cgctgccctg aggacaagca ct #tgccacca    900 ccgtcactca gccctgggcg tagccggaca ggaggagagc agtgatgcgg at #gggtaccc    960 gggcacacca gccctcagag acctgagttc ttctggccac gtggaacctc ga #acccgagc   1020 tcctgcagaa gtggccctgg agattgaggg tccctggaca ctccctatgg ag #atccgggg   1080 agctaggatg gggaacctgc cacagccaga actgaggggc tggccccagg ca #gctcccag   1140 ggggtagaac ggccctgtgc ttaagacact ccctgctgcc ccgtctgagg gt #ggcgatta   1200 aagttgcttc                 #                   #                   #      1210 <210> SEQ ID NO 127 <211> LENGTH: 282 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 127 Met Ser Gly Gly Trp Met Ala Gln Val Gly Al #a Trp Arg Thr Gly Ala   1               5  #                 10  #                 15 Leu Gly Leu Ala Leu Leu Leu Leu Leu Gly Le #u Gly Leu Gly Leu Glu              20      #             25      #             30 Ala Ala Ala Ser Pro Leu Ser Thr Pro Thr Se #r Ala Gln Ala Ala Gly          35          #         40          #         45 Pro Ser Ser Gly Ser Cys Pro Pro Thr Lys Ph #e Gln Cys Arg Thr Ser      50              #     55              #     60 Gly Leu Cys Val Pro Leu Thr Trp Arg Cys As #p Arg Asp Leu Asp Cys  65                  # 70                  # 75                  # 80 Ser Asp Gly Ser Asp Glu Glu Glu Cys Arg Il #e Glu Pro Cys Thr Gln                  85  #                 90  #                 95 Lys Gly Gln Cys Pro Pro Pro Pro Gly Leu Pr #o Cys Pro Cys Thr Gly             100       #           105       #           110 Val Ser Asp Cys Ser Gly Gly Thr Asp Lys Ly #s Leu Arg Asn Cys Ser         115           #       120           #       125 Arg Leu Ala Cys Leu Ala Gly Glu Leu Arg Cy #s Thr Leu Ser Asp Asp     130               #   135               #   140 Cys Ile Pro Leu Thr Trp Arg Cys Asp Gly Hi #s Pro Asp Cys Pro Asp 145                 1 #50                 1 #55                 1 #60 Ser Ser Asp Glu Leu Gly Cys Gly Thr Asn Gl #u Ile Leu Pro Glu Gly                 165   #               170   #               175 Asp Ala Thr Thr Met Gly Pro Pro Val Thr Le #u Glu Ser Val Thr Ser             180       #           185       #           190 Leu Arg Asn Ala Thr Thr Met Gly Pro Pro Va #l Thr Leu Glu Ser Val         195           #       200           #       205 Pro Ser Val Gly Asn Ala Thr Ser Ser Ser Al #a Gly Asp Gln Ser Gly     210               #   215               #   220 Ser Pro Thr Ala Tyr Gly Val Ile Ala Ala Al #a Ala Val Leu Ser Ala 225                 2 #30                 2 #35                 2 #40 Ser Leu Val Thr Ala Thr Leu Leu Leu Leu Se #r Trp Leu Arg Ala Gln                 245   #               250   #               255 Glu Arg Leu Arg Pro Leu Gly Leu Leu Val Al #a Met Lys Glu Ser Leu             260       #           265       #           270 Leu Leu Ser Glu Gln Lys Thr Ser Leu Pro         275           #       280 <210> SEQ ID NO 128 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 128 aagttccagt gccgcaccag tggc           #                   #                24 <210> SEQ ID NO 129 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 129 ttggttccac agccgagctc gtcg           #                   #                24 <210> SEQ ID NO 130 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 130 gaggaggagt gcaggattga gccatgtacc cagaaagggc aatgcccacc   #              50 <210> SEQ ID NO 131 <211> LENGTH: 1843 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (1837) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 131 cccacgcgtc cggtctcgct cgctcgcgca gcggcggcag cagaggtcgc gc #acagatgc     60 gggttagact ggcgggggga ggaggcggag gagggaagga agctgcatgc at #gagaccca    120 cagactcttg caagctggat gccctctgtg gatgaaagat gtatcatgga at #gaacccga    180 gcaatggaga tggatttcta gagcagcagc agcagcagca gcaacctcag tc #cccccaga    240 gactcttggc cgtgatcctg tggtttcagc tggcgctgtg cttcggccct gc #acagctca    300 cgggcgggtt cgatgacctt caagtgtgtg ctgaccccgg cattcccgag aa #tggcttca    360 ggacccccag cggaggggtt ttctttgaag gctctgtagc ccgatttcac tg #ccaagacg    420 gattcaagct gaagggcgct acaaagagac tgtgtttgaa gcattttaat gg #aaccctag    480 gctggatccc aagtgataat tccatctgtg tgcaagaaga ttgccgtatc cc #tcaaatcg    540 aagatgctga gattcataac aagacatata gacatggaga gaagctaatc at #cacttgtc    600 atgaaggatt caagatccgg taccccgacc tacacaatat ggtttcatta tg #tcgcgatg    660 atggaacgtg gaataatctg cccatctgtc aaggctgcct gagacctcta gc #ctcttcta    720 atggctatgt aaacatctct gagctccaga cctccttccc ggtggggact gt #gatctcct    780 atcgctgctt tcccggattt aaacttgatg ggtctgcgta tcttgagtgc tt #acaaaacc    840 ttatctggtc gtccagccca ccccggtgcc ttgctctgga agcccaagtc tg #tccactac    900 ctccaatggt gagtcacgga gatttcgtct gccacccgcg gccttgtgag cg #ctacaacc    960 acggaactgt ggtggagttt tactgcgatc ctggctacag cctcaccagc ga #ctacaagt   1020 acatcacctg ccagtatgga gagtggtttc cttcttatca agtctactgc at #caaatcag   1080 agcaaacgtg gcccagcacc catgagaccc tcctgaccac gtggaagatt gt #ggcgttca   1140 cggcaaccag tgtgctgctg gtgctgctgc tcgtcatcct ggccaggatg tt #ccagacca   1200 agttcaaggc ccactttccc cccagggggc ctccccggag ttccagcagt ga #ccctgact   1260 ttgtggtggt agacggcgtg cccgtcatgc tcccgtccta tgacgaagct gt #gagtggcg   1320 gcttgagtgc cttaggcccc gggtacatgg cctctgtggg ccagggctgc cc #cttacccg   1380 tggacgacca gagcccccca gcataccccg gctcagggga cacggacaca gg #cccagggg   1440 agtcagaaac ctgtgacagc gtctcaggct cttctgagct gctccaaagt ct #gtattcac   1500 ctcccaggtg ccaagagagc acccaccctg cttcggacaa ccctgacata at #tgccagca   1560 cggcagagga ggtggcatcc accagcccag gcatccatca tgcccactgg gt #gttgttcc   1620 taagaaactg attgattaaa aaatttccca aagtgtcctg aagtgtctct tc #aaatacat   1680 gttgatctgt ggagttgatt cctttccttc tcttggtttt agacaaatgt aa #acaaagct   1740 ctgatcctta aaattgctat gctgatagag tggtgagggc tggaagcttg at #caagtcct   1800 gtttcttctt gacacagact gattaaaaat taaaagnaaa aaa     #                 184 #3 <210> SEQ ID NO 132 <211> LENGTH: 490 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 132 Met Tyr His Gly Met Asn Pro Ser Asn Gly As #p Gly Phe Leu Glu Gln   1               5  #                 10  #                 15 Gln Gln Gln Gln Gln Gln Pro Gln Ser Pro Gl #n Arg Leu Leu Ala Val              20      #             25      #             30 Ile Leu Trp Phe Gln Leu Ala Leu Cys Phe Gl #y Pro Ala Gln Leu Thr          35          #         40          #         45 Gly Gly Phe Asp Asp Leu Gln Val Cys Ala As #p Pro Gly Ile Pro Glu      50              #     55              #     60 Asn Gly Phe Arg Thr Pro Ser Gly Gly Val Ph #e Phe Glu Gly Ser Val  65                  # 70                  # 75                  # 80 Ala Arg Phe His Cys Gln Asp Gly Phe Lys Le #u Lys Gly Ala Thr Lys                  85  #                 90  #                 95 Arg Leu Cys Leu Lys His Phe Asn Gly Thr Le #u Gly Trp Ile Pro Ser             100       #           105       #           110 Asp Asn Ser Ile Cys Val Gln Glu Asp Cys Ar #g Ile Pro Gln Ile Glu         115           #       120           #       125 Asp Ala Glu Ile His Asn Lys Thr Tyr Arg Hi #s Gly Glu Lys Leu Ile     130               #   135               #   140 Ile Thr Cys His Glu Gly Phe Lys Ile Arg Ty #r Pro Asp Leu His Asn 145                 1 #50                 1 #55                 1 #60 Met Val Ser Leu Cys Arg Asp Asp Gly Thr Tr #p Asn Asn Leu Pro Ile                 165   #               170   #               175 Cys Gln Gly Cys Leu Arg Pro Leu Ala Ser Se #r Asn Gly Tyr Val Asn             180       #           185       #           190 Ile Ser Glu Leu Gln Thr Ser Phe Pro Val Gl #y Thr Val Ile Ser Tyr         195           #       200           #       205 Arg Cys Phe Pro Gly Phe Lys Leu Asp Gly Se #r Ala Tyr Leu Glu Cys     210               #   215               #   220 Leu Gln Asn Leu Ile Trp Ser Ser Ser Pro Pr #o Arg Cys Leu Ala Leu 225                 2 #30                 2 #35                 2 #40 Glu Ala Gln Val Cys Pro Leu Pro Pro Met Va #l Ser His Gly Asp Phe                 245   #               250   #               255 Val Cys His Pro Arg Pro Cys Glu Arg Tyr As #n His Gly Thr Val Val             260       #           265       #           270 Glu Phe Tyr Cys Asp Pro Gly Tyr Ser Leu Th #r Ser Asp Tyr Lys Tyr         275           #       280           #       285 Ile Thr Cys Gln Tyr Gly Glu Trp Phe Pro Se #r Tyr Gln Val Tyr Cys     290               #   295               #   300 Ile Lys Ser Glu Gln Thr Trp Pro Ser Thr Hi #s Glu Thr Leu Leu Thr 305                 3 #10                 3 #15                 3 #20 Thr Trp Lys Ile Val Ala Phe Thr Ala Thr Se #r Val Leu Leu Val Leu                 325   #               330   #               335 Leu Leu Val Ile Leu Ala Arg Met Phe Gln Th #r Lys Phe Lys Ala His             340       #           345       #           350 Phe Pro Pro Arg Gly Pro Pro Arg Ser Ser Se #r Ser Asp Pro Asp Phe         355           #       360           #       365 Val Val Val Asp Gly Val Pro Val Met Leu Pr #o Ser Tyr Asp Glu Ala     370               #   375               #   380 Val Ser Gly Gly Leu Ser Ala Leu Gly Pro Gl #y Tyr Met Ala Ser Val 385                 3 #90                 3 #95                 4 #00 Gly Gln Gly Cys Pro Leu Pro Val Asp Asp Gl #n Ser Pro Pro Ala Tyr                 405   #               410   #               415 Pro Gly Ser Gly Asp Thr Asp Thr Gly Pro Gl #y Glu Ser Glu Thr Cys             420       #           425       #           430 Asp Ser Val Ser Gly Ser Ser Glu Leu Leu Gl #n Ser Leu Tyr Ser Pro         435           #       440           #       445 Pro Arg Cys Gln Glu Ser Thr His Pro Ala Se #r Asp Asn Pro Asp Ile     450               #   455               #   460 Ile Ala Ser Thr Ala Glu Glu Val Ala Ser Th #r Ser Pro Gly Ile His 465                 4 #70                 4 #75                 4 #80 His Ala His Trp Val Leu Phe Leu Arg Asn                 485   #               490 <210> SEQ ID NO 133 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 133 atctcctatc gctgctttcc cgg            #                   #                23 <210> SEQ ID NO 134 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 134 agccaggatc gcagtaaaac tcc            #                   #                23 <210> SEQ ID NO 135 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 135 atttaaactt gatgggtctg cgtatcttga gtgcttacaa aaccttatct   #              50 <210> SEQ ID NO 136 <211> LENGTH: 1815 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 136 cccacgcgtc cgctccgcgc cctccccccc gcctcccgtg cggtccgtcg gt #ggcctaga     60 gatgctgctg ccgcggttgc agttgtcgcg cacgcctctg cccgccagcc cg #ctccaccg    120 ccgtagcgcc cgagtgtcgg ggggcgcacc cgagtcgggc catgaggccg gg #aaccgcgc    180 tacaggccgt gctgctggcc gtgctgctgg tggggctgcg ggccgcgacg gg #tcgcctgc    240 tgagtgcctc ggatttggac ctcagaggag ggcagccagt ctgccgggga gg #gacacaga    300 ggccttgtta taaagtcatt tacttccatg atacttctcg aagactgaac tt #tgaggaag    360 ccaaagaagc ctgcaggagg gatggaggcc agctagtcag catcgagtct ga #agatgaac    420 agaaactgat agaaaagttc attgaaaacc tcttgccatc tgatggtgac tt #ctggattg    480 ggctcaggag gcgtgaggag aaacaaagca atagcacagc ctgccaggac ct #ttatgctt    540 ggactgatgg cagcatatca caatttagga actggtatgt ggatgagccg tc #ctgcggca    600 gcgaggtctg cgtggtcatg taccatcagc catcggcacc cgctggcatc gg #aggcccct    660 acatgttcca gtggaatgat gaccggtgca acatgaagaa caatttcatt tg #caaatatt    720 ctgatgagaa accagcagtt ccttctagag aagctgaagg tgaggaaaca ga #gctgacaa    780 cacctgtact tccagaagaa acacaggaag aagatgccaa aaaaacattt aa #agaaagta    840 gagaagctgc cttgaatctg gcctacatcc taatccccag cattcccctt ct #cctcctcc    900 ttgtggtcac cacagttgta tgttgggttt ggatctgtag aaaaagaaaa cg #ggagcagc    960 cagaccctag cacaaagaag caacacacca tctggccctc tcctcaccag gg #aaacagcc   1020 cggacctaga ggtctacaat gtcataagaa aacaaagcga agctgactta gc #tgagaccc   1080 ggccagacct gaagaatatt tcattccgag tgtgttcggg agaagccact cc #cgatgaca   1140 tgtcttgtga ctatgacaac atggctgtga acccatcaga aagtgggttt gt #gactctgg   1200 tgagcgtgga gagtggattt gtgaccaatg acatttatga gttctcccca ga #ccaaatgg   1260 ggaggagtaa ggagtctgga tgggtggaaa atgaaatata tggttattag ga #catataaa   1320 aaactgaaac tgacaacaat ggaaaagaaa tgataagcaa aatcctctta tt #ttctataa   1380 ggaaaataca cagaaggtct atgaacaagc ttagatcagg tcctgtggat ga #gcatgtgg   1440 tccccacgac ctcctgttgg acccccacgt tttggctgta tcctttatcc ca #gccagtca   1500 tccagctcga ccttatgaga aggtaccttg cccaggtctg gcacatagta ga #gtctcaat   1560 aaatgtcact tggttggttg tatctaactt ttaagggaca gagctttacc tg #gcagtgat   1620 aaagatgggc tgtggagctt ggaaaaccac ctctgttttc cttgctctat ac #agcagcac   1680 atattatcat acagacagaa aatccagaat cttttcaaag cccacatatg gt #agcacagg   1740 ttggcctgtg catcggcaat tctcatatct gtttttttca aagaataaaa tc #aaataaag   1800 agcaggaaaa aaaaa               #                   #                   #  1815 <210> SEQ ID NO 137 <211> LENGTH: 382 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 137 Met Arg Pro Gly Thr Ala Leu Gln Ala Val Le #u Leu Ala Val Leu Leu   1               5  #                 10  #                 15 Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Le #u Ser Ala Ser Asp Leu              20      #             25      #             30 Asp Leu Arg Gly Gly Gln Pro Val Cys Arg Gl #y Gly Thr Gln Arg Pro          35          #         40          #         45 Cys Tyr Lys Val Ile Tyr Phe His Asp Thr Se #r Arg Arg Leu Asn Phe      50              #     55              #     60 Glu Glu Ala Lys Glu Ala Cys Arg Arg Asp Gl #y Gly Gln Leu Val Ser  65                  # 70                  # 75                  # 80 Ile Glu Ser Glu Asp Glu Gln Lys Leu Ile Gl #u Lys Phe Ile Glu Asn                  85  #                 90  #                 95 Leu Leu Pro Ser Asp Gly Asp Phe Trp Ile Gl #y Leu Arg Arg Arg Glu             100       #           105       #           110 Glu Lys Gln Ser Asn Ser Thr Ala Cys Gln As #p Leu Tyr Ala Trp Thr         115           #       120           #       125 Asp Gly Ser Ile Ser Gln Phe Arg Asn Trp Ty #r Val Asp Glu Pro Ser     130               #   135               #   140 Cys Gly Ser Glu Val Cys Val Val Met Tyr Hi #s Gln Pro Ser Ala Pro 145                 1 #50                 1 #55                 1 #60 Ala Gly Ile Gly Gly Pro Tyr Met Phe Gln Tr #p Asn Asp Asp Arg Cys                 165   #               170   #               175 Asn Met Lys Asn Asn Phe Ile Cys Lys Tyr Se #r Asp Glu Lys Pro Ala             180       #           185       #           190 Val Pro Ser Arg Glu Ala Glu Gly Glu Glu Th #r Glu Leu Thr Thr Pro         195           #       200           #       205 Val Leu Pro Glu Glu Thr Gln Glu Glu Asp Al #a Lys Lys Thr Phe Lys     210               #   215               #   220 Glu Ser Arg Glu Ala Ala Leu Asn Leu Ala Ty #r Ile Leu Ile Pro Ser 225                 2 #30                 2 #35                 2 #40 Ile Pro Leu Leu Leu Leu Leu Val Val Thr Th #r Val Val Cys Trp Val                 245   #               250   #               255 Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pr #o Asp Pro Ser Thr Lys             260       #           265       #           270 Lys Gln His Thr Ile Trp Pro Ser Pro His Gl #n Gly Asn Ser Pro Asp         275           #       280           #       285 Leu Glu Val Tyr Asn Val Ile Arg Lys Gln Se #r Glu Ala Asp Leu Ala     290               #   295               #   300 Glu Thr Arg Pro Asp Leu Lys Asn Ile Ser Ph #e Arg Val Cys Ser Gly 305                 3 #10                 3 #15                 3 #20 Glu Ala Thr Pro Asp Asp Met Ser Cys Asp Ty #r Asp Asn Met Ala Val                 325   #               330   #               335 Asn Pro Ser Glu Ser Gly Phe Val Thr Leu Va #l Ser Val Glu Ser Gly             340       #           345       #           350 Phe Val Thr Asn Asp Ile Tyr Glu Phe Ser Pr #o Asp Gln Met Gly Arg         355           #       360           #       365 Ser Lys Glu Ser Gly Trp Val Glu Asn Glu Il #e Tyr Gly Tyr     370               #   375               #   380 <210> SEQ ID NO 138 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 138 gttcattgaa aacctcttgc catctgatgg tgacttctgg attgggctca   #              50 <210> SEQ ID NO 139 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 139 aagccaaaga agcctgcagg aggg           #                   #                24 <210> SEQ ID NO 140 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 140 cagtccaagc ataaaggtcc tggc           #                   #                24 <210> SEQ ID NO 141 <211> LENGTH: 1514 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 141 ggggtctccc tcagggccgg gaggcacagc ggtccctgct tgctgaaggg ct #ggatgtac     60 gcatccgcag gttcccgcgg acttgggggc gcccgctgag ccccggcgcc cg #cagaagac    120 ttgtgtttgc ctcctgcagc ctcaacccgg agggcagcga gggcctacca cc #atgatcac    180 tggtgtgttc agcatgcgct tgtggacccc agtgggcgtc ctgacctcgc tg #gcgtactg    240 cctgcaccag cggcgggtgg ccctggccga gctgcaggag gccgatggcc ag #tgtccggt    300 cgaccgcagc ctgctgaagt tgaaaatggt gcaggtcgtg tttcgacacg gg #gctcggag    360 tcctctcaag ccgctcccgc tggaggagca ggtagagtgg aacccccagc ta #ttagaggt    420 cccaccccaa actcagtttg attacacagt caccaatcta gctggtggtc cg #aaaccata    480 ttctccttac gactctcaat accatgagac caccctgaag gggggcatgt tt #gctgggca    540 gctgaccaag gtgggcatgc agcaaatgtt tgccttggga gagagactga gg #aagaacta    600 tgtggaagac attccctttc tttcaccaac cttcaaccca caggaggtct tt #attcgttc    660 cactaacatt tttcggaatc tggagtccac ccgttgtttg ctggctgggc tt #ttccagtg    720 tcagaaagaa ggacccatca tcatccacac tgatgaagca gattcagaag tc #ttgtatcc    780 caactaccaa agctgctgga gcctgaggca gagaaccaga ggccggaggc ag #actgcctc    840 tttacagcca ggaatctcag aggatttgaa aaaggtgaag gacaggatgg gc #attgacag    900 tagtgataaa gtggacttct tcatcctcct ggacaacgtg gctgccgagc ag #gcacacaa    960 cctcccaagc tgccccatgc tgaagagatt tgcacggatg atcgaacaga ga #gctgtgga   1020 cacatccttg tacatactgc ccaaggaaga cagggaaagt cttcagatgg ca #gtaggccc   1080 attcctccac atcctagaga gcaacctgct gaaagccatg gactctgcca ct #gcccccga   1140 caagatcaga aagctgtatc tctatgcggc tcatgatgtg accttcatac cg #ctcttaat   1200 gaccctgggg atttttgacc acaaatggcc accgtttgct gttgacctga cc #atggaact   1260 ttaccagcac ctggaatcta aggagtggtt tgtgcagctc tattaccacg gg #aaggagca   1320 ggtgccgaga ggttgccctg atgggctctg cccgctggac atgttcttga at #gccatgtc   1380 agtttatacc ttaagcccag aaaaatacca tgcactctgc tctcaaactc ag #gtgatgga   1440 agttggaaat gaagagtaac tgatttataa aagcaggatg tgttgatttt aa #aataaagt   1500 gcctttatac aatg               #                   #                   #   1514 <210> SEQ ID NO 142 <211> LENGTH: 428 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 142 Met Ile Thr Gly Val Phe Ser Met Arg Leu Tr #p Thr Pro Val Gly Val   1               5  #                 10  #                 15 Leu Thr Ser Leu Ala Tyr Cys Leu His Gln Ar #g Arg Val Ala Leu Ala              20      #             25      #             30 Glu Leu Gln Glu Ala Asp Gly Gln Cys Pro Va #l Asp Arg Ser Leu Leu          35          #         40          #         45 Lys Leu Lys Met Val Gln Val Val Phe Arg Hi #s Gly Ala Arg Ser Pro      50              #     55              #     60 Leu Lys Pro Leu Pro Leu Glu Glu Gln Val Gl #u Trp Asn Pro Gln Leu  65                  # 70                  # 75                  # 80 Leu Glu Val Pro Pro Gln Thr Gln Phe Asp Ty #r Thr Val Thr Asn Leu                  85  #                 90  #                 95 Ala Gly Gly Pro Lys Pro Tyr Ser Pro Tyr As #p Ser Gln Tyr His Glu             100       #           105       #           110 Thr Thr Leu Lys Gly Gly Met Phe Ala Gly Gl #n Leu Thr Lys Val Gly         115           #       120           #       125 Met Gln Gln Met Phe Ala Leu Gly Glu Arg Le #u Arg Lys Asn Tyr Val     130               #   135               #   140 Glu Asp Ile Pro Phe Leu Ser Pro Thr Phe As #n Pro Gln Glu Val Phe 145                 1 #50                 1 #55                 1 #60 Ile Arg Ser Thr Asn Ile Phe Arg Asn Leu Gl #u Ser Thr Arg Cys Leu                 165   #               170   #               175 Leu Ala Gly Leu Phe Gln Cys Gln Lys Glu Gl #y Pro Ile Ile Ile His             180       #           185       #           190 Thr Asp Glu Ala Asp Ser Glu Val Leu Tyr Pr #o Asn Tyr Gln Ser Cys         195           #       200           #       205 Trp Ser Leu Arg Gln Arg Thr Arg Gly Arg Ar #g Gln Thr Ala Ser Leu     210               #   215               #   220 Gln Pro Gly Ile Ser Glu Asp Leu Lys Lys Va #l Lys Asp Arg Met Gly 225                 2 #30                 2 #35                 2 #40 Ile Asp Ser Ser Asp Lys Val Asp Phe Phe Il #e Leu Leu Asp Asn Val                 245   #               250   #               255 Ala Ala Glu Gln Ala His Asn Leu Pro Ser Cy #s Pro Met Leu Lys Arg             260       #           265       #           270 Phe Ala Arg Met Ile Glu Gln Arg Ala Val As #p Thr Ser Leu Tyr Ile         275           #       280           #       285 Leu Pro Lys Glu Asp Arg Glu Ser Leu Gln Me #t Ala Val Gly Pro Phe     290               #   295               #   300 Leu His Ile Leu Glu Ser Asn Leu Leu Lys Al #a Met Asp Ser Ala Thr 305                 3 #10                 3 #15                 3 #20 Ala Pro Asp Lys Ile Arg Lys Leu Tyr Leu Ty #r Ala Ala His Asp Val                 325   #               330   #               335 Thr Phe Ile Pro Leu Leu Met Thr Leu Gly Il #e Phe Asp His Lys Trp             340       #           345       #           350 Pro Pro Phe Ala Val Asp Leu Thr Met Glu Le #u Tyr Gln His Leu Glu         355           #       360           #       365 Ser Lys Glu Trp Phe Val Gln Leu Tyr Tyr Hi #s Gly Lys Glu Gln Val     370               #   375               #   380 Pro Arg Gly Cys Pro Asp Gly Leu Cys Pro Le #u Asp Met Phe Leu Asn 385                 3 #90                 3 #95                 4 #00 Ala Met Ser Val Tyr Thr Leu Ser Pro Glu Ly #s Tyr His Ala Leu Cys                 405   #               410   #               415 Ser Gln Thr Gln Val Met Glu Val Gly Asn Gl #u Glu             420       #           425 <210> SEQ ID NO 143 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 143 ccaactacca aagctgctgg agcc           #                   #                24 <210> SEQ ID NO 144 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 144 gcagctctat taccacggga agga           #                   #                24 <210> SEQ ID NO 145 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 145 tccttcccgt ggtaatagag ctgc           #                   #                24 <210> SEQ ID NO 146 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 146 ggcagagaac cagaggccgg aggagactgc ctctttacag ccagg    #                   #45 <210> SEQ ID NO 147 <211> LENGTH: 1686 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 147 ctcctcttaa catacttgca gctaaaacta aatattgctg cttggggacc tc #cttctagc     60 cttaaatttc agctcatcac cttcacctgc cttggtcatg gctctgctat tc #tccttgat    120 ccttgccatt tgcaccagac ctggattcct agcgtctcca tctggagtgc gg #ctggtggg    180 gggcctccac cgctgtgaag ggcgggtgga ggtggaacag aaaggccagt gg #ggcaccgt    240 gtgtgatgac ggctgggaca ttaaggacgt ggctgtgttg tgccgggagc tg #ggctgtgg    300 agctgccagc ggaaccccta gtggtatttt gtatgagcca ccagcagaaa aa #gagcaaaa    360 ggtcctcatc caatcagtca gttgcacagg aacagaagat acattggctc ag #tgtgagca    420 agaagaagtt tatgattgtt cacatgatga agatgctggg gcatcgtgtg ag #aacccaga    480 gagctctttc tccccagtcc cagagggtgt caggctggct gacggccctg gg #cattgcaa    540 gggacgcgtg gaagtgaagc accagaacca gtggtatacc gtgtgccaga ca #ggctggag    600 cctccgggcc gcaaaggtgg tgtgccggca gctgggatgt gggagggctg ta #ctgactca    660 aaaacgctgc aacaagcatg cctatggccg aaaacccatc tggctgagcc ag #atgtcatg    720 ctcaggacga gaagcaaccc ttcaggattg cccttctggg ccttggggga ag #aacacctg    780 caaccatgat gaagacacgt gggtcgaatg tgaagatccc tttgacttga ga #ctagtagg    840 aggagacaac ctctgctctg ggcgactgga ggtgctgcac aagggcgtat gg #ggctctgt    900 ctgtgatgac aactggggag aaaaggagga ccaggtggta tgcaagcaac tg #ggctgtgg    960 gaagtccctc tctccctcct tcagagaccg gaaatgctat ggccctgggg tt #ggccgcat   1020 ctggctggat aatgttcgtt gctcagggga ggagcagtcc ctggagcagt gc #cagcacag   1080 attttggggg tttcacgact gcacccacca ggaagatgtg gctgtcatct gc #tcagtgta   1140 ggtgggcatc atctaatctg ttgagtgcct gaatagaaga aaaacacaga ag #aagggagc   1200 atttactgtc tacatgactg catgggatga acactgatct tcttctgccc tt #ggactggg   1260 acttatactt ggtgcccctg attctcaggc cttcagagtt ggatcagaac tt #acaacatc   1320 aggtctagtt ctcaggccat cagacatagt ttggaactac atcaccacct tt #cctatgtc   1380 tccacattgc acacagcaga ttcccagcct ccataattgt gtgtatcaac ta #cttaaata   1440 cattctcaca cacacacaca cacacacaca cacacacaca cacacataca cc #atttgtcc   1500 tgtttctctg aagaactctg acaaaataca gattttggta ctgaaagaga tt #ctagagga   1560 acggaatttt aaggataaat tttctgaatt ggttatgggg tttctgaaat tg #gctctata   1620 atctaattag atataaaatt ctggtaactt tatttacaat aataaagata gc #actatgtg   1680 ttcaaa                  #                   #                   #         1686 <210> SEQ ID NO 148 <211> LENGTH: 347 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 148 Met Ala Leu Leu Phe Ser Leu Ile Leu Ala Il #e Cys Thr Arg Pro Gly   1               5  #                 10  #                 15 Phe Leu Ala Ser Pro Ser Gly Val Arg Leu Va #l Gly Gly Leu His Arg              20      #             25      #             30 Cys Glu Gly Arg Val Glu Val Glu Gln Lys Gl #y Gln Trp Gly Thr Val          35          #         40          #         45 Cys Asp Asp Gly Trp Asp Ile Lys Asp Val Al #a Val Leu Cys Arg Glu      50              #     55              #     60 Leu Gly Cys Gly Ala Ala Ser Gly Thr Pro Se #r Gly Ile Leu Tyr Glu  65                  # 70                  # 75                  # 80 Pro Pro Ala Glu Lys Glu Gln Lys Val Leu Il #e Gln Ser Val Ser Cys                  85  #                 90  #                 95 Thr Gly Thr Glu Asp Thr Leu Ala Gln Cys Gl #u Gln Glu Glu Val Tyr             100       #           105       #           110 Asp Cys Ser His Asp Glu Asp Ala Gly Ala Se #r Cys Glu Asn Pro Glu         115           #       120           #       125 Ser Ser Phe Ser Pro Val Pro Glu Gly Val Ar #g Leu Ala Asp Gly Pro     130               #   135               #   140 Gly His Cys Lys Gly Arg Val Glu Val Lys Hi #s Gln Asn Gln Trp Tyr 145                 1 #50                 1 #55                 1 #60 Thr Val Cys Gln Thr Gly Trp Ser Leu Arg Al #a Ala Lys Val Val Cys                 165   #               170   #               175 Arg Gln Leu Gly Cys Gly Arg Ala Val Leu Th #r Gln Lys Arg Cys Asn             180       #           185       #           190 Lys His Ala Tyr Gly Arg Lys Pro Ile Trp Le #u Ser Gln Met Ser Cys         195           #       200           #       205 Ser Gly Arg Glu Ala Thr Leu Gln Asp Cys Pr #o Ser Gly Pro Trp Gly     210               #   215               #   220 Lys Asn Thr Cys Asn His Asp Glu Asp Thr Tr #p Val Glu Cys Glu Asp 225                 2 #30                 2 #35                 2 #40 Pro Phe Asp Leu Arg Leu Val Gly Gly Asp As #n Leu Cys Ser Gly Arg                 245   #               250   #               255 Leu Glu Val Leu His Lys Gly Val Trp Gly Se #r Val Cys Asp Asp Asn             260       #           265       #           270 Trp Gly Glu Lys Glu Asp Gln Val Val Cys Ly #s Gln Leu Gly Cys Gly         275           #       280           #       285 Lys Ser Leu Ser Pro Ser Phe Arg Asp Arg Ly #s Cys Tyr Gly Pro Gly     290               #   295               #   300 Val Gly Arg Ile Trp Leu Asp Asn Val Arg Cy #s Ser Gly Glu Glu Gln 305                 3 #10                 3 #15                 3 #20 Ser Leu Glu Gln Cys Gln His Arg Phe Trp Gl #y Phe His Asp Cys Thr                 325   #               330   #               335 His Gln Glu Asp Val Ala Val Ile Cys Ser Va #l             340       #           345 <210> SEQ ID NO 149 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 149 ttcagctcat caccttcacc tgcc           #                   #                24 <210> SEQ ID NO 150 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 150 ggctcataca aaataccact aggg           #                   #                24 <210> SEQ ID NO 151 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 151 gggcctccac cgctgtgaag ggcgggtgga ggtggaacag aaaggccagt   #              50 <210> SEQ ID NO 152 <211> LENGTH: 1427 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 152 actgcactcg gttctatcga ttgaattccc cggggatcct ctagagatcc ct #cgacctcg     60 acccacgcgt ccgcggacgc gtgggcggac gcgtgggccg gctaccagga ag #agtctgcc    120 gaaggtgaag gccatggact tcatcacctc cacagccatc ctgcccctgc tg #ttcggctg    180 cctgggcgtc ttcggcctct tccggctgct gcagtgggtg cgcgggaagg cc #tacctgcg    240 gaatgctgtg gtggtgatca caggcgccac ctcagggctg ggcaaagaat gt #gcaaaagt    300 cttctatgct gcgggtgcta aactggtgct ctgtggccgg aatggtgggg cc #ctagaaga    360 gctcatcaga gaacttaccg cttctcatgc caccaaggtg cagacacaca ag #ccttactt    420 ggtgaccttc gacctcacag actctggggc catagttgca gcagcagctg ag #atcctgca    480 gtgctttggc tatgtcgaca tacttgtcaa caatgctggg atcagctacc gt #ggtaccat    540 catggacacc acagtggatg tggacaagag ggtcatggag acaaactact tt #ggcccagt    600 tgctctaacg aaagcactcc tgccctccat gatcaagagg aggcaaggcc ac #attgtcgc    660 catcagcagc atccagggca agatgagcat tccttttcga tcagcatatg ca #gcctccaa    720 gcacgcaacc caggctttct ttgactgtct gcgtgccgag atggaacagt at #gaaattga    780 ggtgaccgtc atcagccccg gctacatcca caccaacctc tctgtaaatg cc #atcaccgc    840 ggatggatct aggtatggag ttatggacac caccacagcc cagggccgaa gc #cctgtgga    900 ggtggcccag gatgttcttg ctgctgtggg gaagaagaag aaagatgtga tc #ctggctga    960 cttactgcct tccttggctg tttatcttcg aactctggct cctgggctct tc #ttcagcct   1020 catggcctcc agggccagaa aagagcggaa atccaagaac tcctagtact ct #gaccagcc   1080 agggccaggg cagagaagca gcactcttag gcttgcttac tctacaaggg ac #agttgcat   1140 ttgttgagac tttaatggag atttgtctca caagtgggaa agactgaaga aa #cacatctc   1200 gtgcagatct gctggcagag gacaatcaaa aacgacaaca agcttcttcc ca #gggtgagg   1260 ggaaacactt aaggaataaa tatggagctg gggtttaaca ctaaaaacta ga #aataaaca   1320 tctcaaacag taaaaaaaaa aaaaaagggc ggccgcgact ctagagtcga cc #tgcagaag   1380 cttggccgcc atggcccaac ttgtttattg cagcttataa tggttac    #              1427 <210> SEQ ID NO 153 <211> LENGTH: 310 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153 Met Asp Phe Ile Thr Ser Thr Ala Ile Leu Pr #o Leu Leu Phe Gly Cys   1               5  #                 10  #                 15 Leu Gly Val Phe Gly Leu Phe Arg Leu Leu Gl #n Trp Val Arg Gly Lys              20      #             25      #             30 Ala Tyr Leu Arg Asn Ala Val Val Val Ile Th #r Gly Ala Thr Ser Gly          35          #         40          #         45 Leu Gly Lys Glu Cys Ala Lys Val Phe Tyr Al #a Ala Gly Ala Lys Leu      50              #     55              #     60 Val Leu Cys Gly Arg Asn Gly Gly Ala Leu Gl #u Glu Leu Ile Arg Glu  65                  # 70                  # 75                  # 80 Leu Thr Ala Ser His Ala Thr Lys Val Gln Th #r His Lys Pro Tyr Leu                  85  #                 90  #                 95 Val Thr Phe Asp Leu Thr Asp Ser Gly Ala Il #e Val Ala Ala Ala Ala             100       #           105       #           110 Glu Ile Leu Gln Cys Phe Gly Tyr Val Asp Il #e Leu Val Asn Asn Ala         115           #       120           #       125 Gly Ile Ser Tyr Arg Gly Thr Ile Met Asp Th #r Thr Val Asp Val Asp     130               #   135               #   140 Lys Arg Val Met Glu Thr Asn Tyr Phe Gly Pr #o Val Ala Leu Thr Lys 145                 1 #50                 1 #55                 1 #60 Ala Leu Leu Pro Ser Met Ile Lys Arg Arg Gl #n Gly His Ile Val Ala                 165   #               170   #               175 Ile Ser Ser Ile Gln Gly Lys Met Ser Ile Pr #o Phe Arg Ser Ala Tyr             180       #           185       #           190 Ala Ala Ser Lys His Ala Thr Gln Ala Phe Ph #e Asp Cys Leu Arg Ala         195           #       200           #       205 Glu Met Glu Gln Tyr Glu Ile Glu Val Thr Va #l Ile Ser Pro Gly Tyr     210               #   215               #   220 Ile His Thr Asn Leu Ser Val Asn Ala Ile Th #r Ala Asp Gly Ser Arg 225                 2 #30                 2 #35                 2 #40 Tyr Gly Val Met Asp Thr Thr Thr Ala Gln Gl #y Arg Ser Pro Val Glu                 245   #               250   #               255 Val Ala Gln Asp Val Leu Ala Ala Val Gly Ly #s Lys Lys Lys Asp Val             260       #           265       #           270 Ile Leu Ala Asp Leu Leu Pro Ser Leu Ala Va #l Tyr Leu Arg Thr Leu         275           #       280           #       285 Ala Pro Gly Leu Phe Phe Ser Leu Met Ala Se #r Arg Ala Arg Lys Glu     290               #   295               #   300 Arg Lys Ser Lys Asn Ser 305                 3 #10 <210> SEQ ID NO 154 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 154 ggtgctaaac tggtgctctg tggc           #                   #                24 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 155 cagggcaaga tgagcattcc             #                   #                   # 20 <210> SEQ ID NO 156 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 156 tcatactgtt ccatctcggc acgc           #                   #                24 <210> SEQ ID NO 157 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 157 aatggtgggg ccctagaaga gctcatcaga gaactcaccg cttctcatgc   #              50 <210> SEQ ID NO 158 <211> LENGTH: 1771 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 158 cccacgcgtc cgctggtgtt agatcgagca accctctaaa agcagtttag ag #tggtaaaa     60 aaaaaaaaaa acacaccaaa cgctcgcagc cacaaaaggg atgaaatttc tt #ctggacat    120 cctcctgctt ctcccgttac tgatcgtctg ctccctagag tccttcgtga ag #ctttttat    180 tcctaagagg agaaaatcag tcaccggcga aatcgtgctg attacaggag ct #gggcatgg    240 aattgggaga ctgactgcct atgaatttgc taaacttaaa agcaagctgg tt #ctctggga    300 tataaataag catggactgg aggaaacagc tgccaaatgc aagggactgg gt #gccaaggt    360 tcataccttt gtggtagact gcagcaaccg agaagatatt tacagctctg ca #aagaaggt    420 gaaggcagaa attggagatg ttagtatttt agtaaataat gctggtgtag tc #tatacatc    480 agatttgttt gctacacaag atcctcagat tgaaaagact tttgaagtta at #gtacttgc    540 acatttctgg actacaaagg catttcttcc tgcaatgacg aagaataacc at #ggccatat    600 tgtcactgtg gcttcggcag ctggacatgt ctcggtcccc ttcttactgg ct #tactgttc    660 aagcaagttt gctgctgttg gatttcataa aactttgaca gatgaactgg ct #gccttaca    720 aataactgga gtcaaaacaa catgtctgtg tcctaatttc gtaaacactg gc #ttcatcaa    780 aaatccaagt acaagtttgg gacccactct ggaacctgag gaagtggtaa ac #aggctgat    840 gcatgggatt ctgactgagc agaagatgat ttttattcca tcttctatag ct #tttttaac    900 aacattggaa aggatccttc ctgagcgttt cctggcagtt ttaaaacgaa aa #atcagtgt    960 taagtttgat gcagttattg gatataaaat gaaagcgcaa taagcaccta gt #tttctgaa   1020 aactgattta ccaggtttag gttgatgtca tctaatagtg ccagaatttt aa #tgtttgaa   1080 cttctgtttt ttctaattat ccccatttct tcaatatcat ttttgaggct tt #ggcagtct   1140 tcatttacta ccacttgttc tttagccaaa agctgattac atatgatata aa #cagagaaa   1200 tacctttaga ggtgacttta aggaaaatga agaaaaagaa ccaaaatgac tt #tattaaaa   1260 taatttccaa gattatttgt ggctcacctg aaggctttgc aaaatttgta cc #ataaccgt   1320 ttatttaaca tatattttta tttttgattg cacttaaatt ttgtataatt tg #tgtttctt   1380 tttctgttct acataaaatc agaaacttca agctctctaa ataaaatgaa gg #actatatc   1440 tagtggtatt tcacaatgaa tatcatgaac tctcaatggg taggtttcat cc #tacccatt   1500 gccactctgt ttcctgagag atacctcaca ttccaatgcc aaacatttct gc #acagggaa   1560 gctagaggtg gatacacgtg ttgcaagtat aaaagcatca ctgggattta ag #gagaattg   1620 agagaatgta cccacaaatg gcagcaataa taaatggatc acacttaaaa aa #aaaaaaaa   1680 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa #aaaaaaaa   1740 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a         #                   #        1771 <210> SEQ ID NO 159 <211> LENGTH: 300 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 159 Met Lys Phe Leu Leu Asp Ile Leu Leu Leu Le #u Pro Leu Leu Ile Val   1               5  #                 10  #                 15 Cys Ser Leu Glu Ser Phe Val Lys Leu Phe Il #e Pro Lys Arg Arg Lys              20      #             25      #             30 Ser Val Thr Gly Glu Ile Val Leu Ile Thr Gl #y Ala Gly His Gly Ile          35          #         40          #         45 Gly Arg Leu Thr Ala Tyr Glu Phe Ala Lys Le #u Lys Ser Lys Leu Val      50              #     55              #     60 Leu Trp Asp Ile Asn Lys His Gly Leu Glu Gl #u Thr Ala Ala Lys Cys  65                  # 70                  # 75                  # 80 Lys Gly Leu Gly Ala Lys Val His Thr Phe Va #l Val Asp Cys Ser Asn                  85  #                 90  #                 95 Arg Glu Asp Ile Tyr Ser Ser Ala Lys Lys Va #l Lys Ala Glu Ile Gly             100       #           105       #           110 Asp Val Ser Ile Leu Val Asn Asn Ala Gly Va #l Val Tyr Thr Ser Asp         115           #       120           #       125 Leu Phe Ala Thr Gln Asp Pro Gln Ile Glu Ly #s Thr Phe Glu Val Asn     130               #   135               #   140 Val Leu Ala His Phe Trp Thr Thr Lys Ala Ph #e Leu Pro Ala Met Thr 145                 1 #50                 1 #55                 1 #60 Lys Asn Asn His Gly His Ile Val Thr Val Al #a Ser Ala Ala Gly His                 165   #               170   #               175 Val Ser Val Pro Phe Leu Leu Ala Tyr Cys Se #r Ser Lys Phe Ala Ala             180       #           185       #           190 Val Gly Phe His Lys Thr Leu Thr Asp Glu Le #u Ala Ala Leu Gln Ile         195           #       200           #       205 Thr Gly Val Lys Thr Thr Cys Leu Cys Pro As #n Phe Val Asn Thr Gly     210               #   215               #   220 Phe Ile Lys Asn Pro Ser Thr Ser Leu Gly Pr #o Thr Leu Glu Pro Glu 225                 2 #30                 2 #35                 2 #40 Glu Val Val Asn Arg Leu Met His Gly Ile Le #u Thr Glu Gln Lys Met                 245   #               250   #               255 Ile Phe Ile Pro Ser Ser Ile Ala Phe Leu Th #r Thr Leu Glu Arg Ile             260       #           265       #           270 Leu Pro Glu Arg Phe Leu Ala Val Leu Lys Ar #g Lys Ile Ser Val Lys         275           #       280           #       285 Phe Asp Ala Val Ile Gly Tyr Lys Met Lys Al #a Gln     290               #   295               #   300 <210> SEQ ID NO 160 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 160 ggtgaaggca gaaattggag atg            #                   #                23 <210> SEQ ID NO 161 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 161 atcccatgca tcagcctgtt tacc           #                   #                24 <210> SEQ ID NO 162 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 162 gctggtgtag tctatacatc agatttgttt gctacacaag atcctcag   #                48 <210> SEQ ID NO 163 <211> LENGTH: 2076 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 163 cccacgcgtc cgcggacgcg tgggtcgact agttctagat cgcgagcggc cg #cccgcggc     60 tcagggagga gcaccgactg cgccgcaccc tgagagatgg ttggtgccat gt #ggaaggtg    120 attgtttcgc tggtcctgtt gatgcctggc ccctgtgatg ggctgtttcg ct #ccctatac    180 agaagtgttt ccatgccacc taagggagac tcaggacagc cattatttct ca #ccccttac    240 attgaagctg ggaagatcca aaaaggaaga gaattgagtt tggtcggccc tt #tcccagga    300 ctgaacatga agagttatgc cggcttcctc accgtgaata agacttacaa ca #gcaacctc    360 ttcttctggt tcttcccagc tcagatacag ccagaagatg ccccagtagt tc #tctggcta    420 cagggtgggc cgggaggttc atccatgttt ggactctttg tggaacatgg gc #cttatgtt    480 gtcacaagta acatgacctt gcgtgacaga gacttcccct ggaccacaac gc #tctccatg    540 ctttacattg acaatccagt gggcacaggc ttcagtttta ctgatgatac cc #acggatat    600 gcagtcaatg aggacgatgt agcacgggat ttatacagtg cactaattca gt #ttttccag    660 atatttcctg aatataaaaa taatgacttt tatgtcactg gggagtctta tg #cagggaaa    720 tatgtgccag ccattgcaca cctcatccat tccctcaacc ctgtgagaga gg #tgaagatc    780 aacctgaacg gaattgctat tggagatgga tattctgatc ccgaatcaat ta #tagggggc    840 tatgcagaat tcctgtacca aattggcttg ttggatgaga agcaaaaaaa gt #acttccag    900 aagcagtgcc atgaatgcat agaacacatc aggaagcaga actggtttga gg #cctttgaa    960 atactggata aactactaga tggcgactta acaagtgatc cttcttactt cc #agaatgtt   1020 acaggatgta gtaattacta taactttttg cggtgcacgg aacctgagga tc #agctttac   1080 tatgtgaaat ttttgtcact cccagaggtg agacaagcca tccacgtggg ga #atcagact   1140 tttaatgatg gaactatagt tgaaaagtac ttgcgagaag atacagtaca gt #cagttaag   1200 ccatggttaa ctgaaatcat gaataattat aaggttctga tctacaatgg cc #aactggac   1260 atcatcgtgg cagctgccct gacagagcgc tccttgatgg gcatggactg ga #aaggatcc   1320 caggaataca agaaggcaga aaaaaaagtt tggaagatct ttaaatctga ca #gtgaagtg   1380 gctggttaca tccggcaagc gggtgacttc catcaggtaa ttattcgagg tg #gaggacat   1440 attttaccct atgaccagcc tctgagagct tttgacatga ttaatcgatt ca #tttatgga   1500 aaaggatggg atccttatgt tggataaact accttcccaa aagagaacat ca #gaggtttt   1560 cattgctgaa aagaaaatcg taaaaacaga aaatgtcata ggaataaaaa aa #ttatcttt   1620 tcatatctgc aagatttttt tcatcaataa aaattatcct tgaaacaagt ga #gcttttgt   1680 ttttgggggg agatgtttac tacaaaatta acatgagtac atgagtaaga at #tacattat   1740 ttaacttaaa ggatgaaagg tatggatgat gtgacactga gacaagatgt at #aaatgaaa   1800 ttttagggtc ttgaatagga agttttaatt tcttctaaga gtaagtgaaa ag #tgcagttg   1860 taacaaacaa agctgtaaca tctttttctg ccaataacag aagtttggca tg #ccgtgaag   1920 gtgtttggaa atattattgg ataagaatag ctcaattatc ccaaataaat gg #atgaagct   1980 ataatagttt tggggaaaag attctcaaat gtataaagtc ttagaacaaa ag #aattcttt   2040 gaaataaaaa tattatatat aaaagtaaaa aaaaaa       #                   #     2076 <210> SEQ ID NO 164 <211> LENGTH: 476 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 164 Met Val Gly Ala Met Trp Lys Val Ile Val Se #r Leu Val Leu Leu Met   1               5  #                 10  #                 15 Pro Gly Pro Cys Asp Gly Leu Phe Arg Ser Le #u Tyr Arg Ser Val Ser              20      #             25      #             30 Met Pro Pro Lys Gly Asp Ser Gly Gln Pro Le #u Phe Leu Thr Pro Tyr          35          #         40          #         45 Ile Glu Ala Gly Lys Ile Gln Lys Gly Arg Gl #u Leu Ser Leu Val Gly      50              #     55              #     60 Pro Phe Pro Gly Leu Asn Met Lys Ser Tyr Al #a Gly Phe Leu Thr Val  65                  # 70                  # 75                  # 80 Asn Lys Thr Tyr Asn Ser Asn Leu Phe Phe Tr #p Phe Phe Pro Ala Gln                  85  #                 90  #                 95 Ile Gln Pro Glu Asp Ala Pro Val Val Leu Tr #p Leu Gln Gly Gly Pro             100       #           105       #           110 Gly Gly Ser Ser Met Phe Gly Leu Phe Val Gl #u His Gly Pro Tyr Val         115           #       120           #       125 Val Thr Ser Asn Met Thr Leu Arg Asp Arg As #p Phe Pro Trp Thr Thr     130               #   135               #   140 Thr Leu Ser Met Leu Tyr Ile Asp Asn Pro Va #l Gly Thr Gly Phe Ser 145                 1 #50                 1 #55                 1 #60 Phe Thr Asp Asp Thr His Gly Tyr Ala Val As #n Glu Asp Asp Val Ala                 165   #               170   #               175 Arg Asp Leu Tyr Ser Ala Leu Ile Gln Phe Ph #e Gln Ile Phe Pro Glu             180       #           185       #           190 Tyr Lys Asn Asn Asp Phe Tyr Val Thr Gly Gl #u Ser Tyr Ala Gly Lys         195           #       200           #       205 Tyr Val Pro Ala Ile Ala His Leu Ile His Se #r Leu Asn Pro Val Arg     210               #   215               #   220 Glu Val Lys Ile Asn Leu Asn Gly Ile Ala Il #e Gly Asp Gly Tyr Ser 225                 2 #30                 2 #35                 2 #40 Asp Pro Glu Ser Ile Ile Gly Gly Tyr Ala Gl #u Phe Leu Tyr Gln Ile                 245   #               250   #               255 Gly Leu Leu Asp Glu Lys Gln Lys Lys Tyr Ph #e Gln Lys Gln Cys His             260       #           265       #           270 Glu Cys Ile Glu His Ile Arg Lys Gln Asn Tr #p Phe Glu Ala Phe Glu         275           #       280           #       285 Ile Leu Asp Lys Leu Leu Asp Gly Asp Leu Th #r Ser Asp Pro Ser Tyr     290               #   295               #   300 Phe Gln Asn Val Thr Gly Cys Ser Asn Tyr Ty #r Asn Phe Leu Arg Cys 305                 3 #10                 3 #15                 3 #20 Thr Glu Pro Glu Asp Gln Leu Tyr Tyr Val Ly #s Phe Leu Ser Leu Pro                 325   #               330   #               335 Glu Val Arg Gln Ala Ile His Val Gly Asn Gl #n Thr Phe Asn Asp Gly             340       #           345       #           350 Thr Ile Val Glu Lys Tyr Leu Arg Glu Asp Th #r Val Gln Ser Val Lys         355           #       360           #       365 Pro Trp Leu Thr Glu Ile Met Asn Asn Tyr Ly #s Val Leu Ile Tyr Asn     370               #   375               #   380 Gly Gln Leu Asp Ile Ile Val Ala Ala Ala Le #u Thr Glu Arg Ser Leu 385                 3 #90                 3 #95                 4 #00 Met Gly Met Asp Trp Lys Gly Ser Gln Glu Ty #r Lys Lys Ala Glu Lys                 405   #               410   #               415 Lys Val Trp Lys Ile Phe Lys Ser Asp Ser Gl #u Val Ala Gly Tyr Ile             420       #           425       #           430 Arg Gln Ala Gly Asp Phe His Gln Val Ile Il #e Arg Gly Gly Gly His         435           #       440           #       445 Ile Leu Pro Tyr Asp Gln Pro Leu Arg Ala Ph #e Asp Met Ile Asn Arg     450               #   455               #   460 Phe Ile Tyr Gly Lys Gly Trp Asp Pro Tyr Va #l Gly 465                 4 #70                 4 #75 <210> SEQ ID NO 165 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 165 ttccatgcca cctaagggag actc           #                   #                24 <210> SEQ ID NO 166 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 166 tggatgaggt gtgcaatggc tggc           #                   #                24 <210> SEQ ID NO 167 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 167 agctctcaga ggctggtcat aggg           #                   #                24 <210> SEQ ID NO 168 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 168 gtcggccctt tcccaggact gaacatgaag agttatgccg gcttcctcac   #              50 <210> SEQ ID NO 169 <211> LENGTH: 2477 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 169 cgagggcttt tccggctccg gaatggcaca tgtgggaatc ccagtcttgt tg #gctacaac     60 atttttccct ttcctaacaa gttctaacag ctgttctaac agctagtgat ca #ggggttct    120 tcttgctgga gaagaaaggg ctgagggcag agcagggcac tctcactcag gg #tgaccagc    180 tccttgcctc tctgtggata acagagcatg agaaagtgaa gagatgcagc gg #agtgaggt    240 gatggaagtc taaaatagga aggaattttg tgtgcaatat cagactctgg ga #gcagttga    300 cctggagagc ctgggggagg gcctgcctaa caagctttca aaaaacagga gc #gacttcca    360 ctgggctggg ataagacgtg ccggtaggat agggaagact gggtttagtc ct #aatatcaa    420 attgactggc tgggtgaact tcaacagcct tttaacctct ctgggagatg aa #aacgatgg    480 cttaaggggc cagaaataga gatgctttgt aaaataaaat tttaaaaaaa gc #aagtattt    540 tatagcataa aggctagaga ccaaaataga taacaggatt ccctgaacat tc #ctaagagg    600 gagaaagtat gttaaaaata gaaaaaccaa aatgcagaag gaggagactc ac #agagctaa    660 accaggatgg ggaccctggg tcaggccagc ctctttgctc ctcccggaaa tt #atttttgg    720 tctgaccact ctgccttgtg ttttgcagaa tcatgtgagg gccaaccggg ga #aggtggag    780 cagatgagca cacacaggag ccgtctcctc accgccgccc ctctcagcat gg #aacagagg    840 cagccctggc cccgggccct ggaggtggac agccgctctg tggtcctgct ct #cagtggtc    900 tgggtgctgc tggccccccc agcagccggc atgcctcagt tcagcacctt cc #actctgag    960 aatcgtgact ggaccttcaa ccacttgacc gtccaccaag ggacgggggc cg #tctatgtg   1020 ggggccatca accgggtcta taagctgaca ggcaacctga ccatccaggt gg #ctcataag   1080 acagggccag aagaggacaa caagtctcgt tacccgcccc tcatcgtgca gc #cctgcagc   1140 gaagtgctca ccctcaccaa caatgtcaac aagctgctca tcattgacta ct #ctgagaac   1200 cgcctgctgg cctgtgggag cctctaccag ggggtctgca agctgctgcg gc #tggatgac   1260 ctcttcatcc tggtggagcc atcccacaag aaggagcact acctgtccag tg #tcaacaag   1320 acgggcacca tgtacggggt gattgtgcgc tctgagggtg aggatggcaa gc #tcttcatc   1380 ggcacggctg tggatgggaa gcaggattac ttcccgaccc tgtccagccg ga #agctgccc   1440 cgagaccctg agtcctcagc catgctcgac tatgagctac acagcgattt tg #tctcctct   1500 ctcatcaaga tcccttcaga caccctggcc ctggtctccc actttgacat ct #tctacatc   1560 tacggctttg ctagtggggg ctttgtctac tttctcactg tccagcccga ga #cccctgag   1620 ggtgtggcca tcaactccgc tggagacctc ttctacacct cacgcatcgt gc #ggctctgc   1680 aaggatgacc ccaagttcca ctcatacgtg tccctgccct tcggctgcac cc #gggccggg   1740 gtggaatacc gcctcctgca ggctgcttac ctggccaagc ctggggactc ac #tggcccag   1800 gccttcaata tcaccagcca ggacgatgta ctctttgcca tcttctccaa ag #ggcagaag   1860 cagtatcacc acccgcccga tgactctgcc ctgtgtgcct tccctatccg gg #ccatcaac   1920 ttgcagatca aggagcgcct gcagtcctgc taccagggcg agggcaacct gg #agctcaac   1980 tggctgctgg ggaaggacgt ccagtgcacg aaggcgcctg tccccatcga tg #ataacttc   2040 tgtggactgg acatcaacca gcccctggga ggctcaactc cagtggaggg cc #tgaccctg   2100 tacaccacca gcagggaccg catgacctct gtggcctcct acgtttacaa cg #gctacagc   2160 gtggtttttg tggggactaa gagtggcaag ctgaaaaagg taagagtcta tg #agttcaga   2220 tgctccaatg ccattcacct cctcagcaaa gagtccctct tggaaggtag ct #attggtgg   2280 agatttaact ataggcaact ttattttctt ggggaacaaa ggtgaaatgg gg #aggtaaga   2340 aggggttaat tttgtgactt agcttctagc tacttcctcc agccatcagt ca #ttgggtat   2400 gtaaggaatg caagcgtatt tcaatatttc ccaaacttta agaaaaaact tt #aagaaggt   2460 acatctgcaa aagcaaa              #                   #                   # 2477 <210> SEQ ID NO 170 <211> LENGTH: 552 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 170 Met Gly Thr Leu Gly Gln Ala Ser Leu Phe Al #a Pro Pro Gly Asn Tyr   1               5  #                 10  #                 15 Phe Trp Ser Asp His Ser Ala Leu Cys Phe Al #a Glu Ser Cys Glu Gly              20      #             25      #             30 Gln Pro Gly Lys Val Glu Gln Met Ser Thr Hi #s Arg Ser Arg Leu Leu          35          #         40          #         45 Thr Ala Ala Pro Leu Ser Met Glu Gln Arg Gl #n Pro Trp Pro Arg Ala      50              #     55              #     60 Leu Glu Val Asp Ser Arg Ser Val Val Leu Le #u Ser Val Val Trp Val  65                  # 70                  # 75                  # 80 Leu Leu Ala Pro Pro Ala Ala Gly Met Pro Gl #n Phe Ser Thr Phe His                  85  #                 90  #                 95 Ser Glu Asn Arg Asp Trp Thr Phe Asn His Le #u Thr Val His Gln Gly             100       #           105       #           110 Thr Gly Ala Val Tyr Val Gly Ala Ile Asn Ar #g Val Tyr Lys Leu Thr         115           #       120           #       125 Gly Asn Leu Thr Ile Gln Val Ala His Lys Th #r Gly Pro Glu Glu Asp     130               #   135               #   140 Asn Lys Ser Arg Tyr Pro Pro Leu Ile Val Gl #n Pro Cys Ser Glu Val 145                 1 #50                 1 #55                 1 #60 Leu Thr Leu Thr Asn Asn Val Asn Lys Leu Le #u Ile Ile Asp Tyr Ser                 165   #               170   #               175 Glu Asn Arg Leu Leu Ala Cys Gly Ser Leu Ty #r Gln Gly Val Cys Lys             180       #           185       #           190 Leu Leu Arg Leu Asp Asp Leu Phe Ile Leu Va #l Glu Pro Ser His Lys         195           #       200           #       205 Lys Glu His Tyr Leu Ser Ser Val Asn Lys Th #r Gly Thr Met Tyr Gly     210               #   215               #   220 Val Ile Val Arg Ser Glu Gly Glu Asp Gly Ly #s Leu Phe Ile Gly Thr 225                 2 #30                 2 #35                 2 #40 Ala Val Asp Gly Lys Gln Asp Tyr Phe Pro Th #r Leu Ser Ser Arg Lys                 245   #               250   #               255 Leu Pro Arg Asp Pro Glu Ser Ser Ala Met Le #u Asp Tyr Glu Leu His             260       #           265       #           270 Ser Asp Phe Val Ser Ser Leu Ile Lys Ile Pr #o Ser Asp Thr Leu Ala         275           #       280           #       285 Leu Val Ser His Phe Asp Ile Phe Tyr Ile Ty #r Gly Phe Ala Ser Gly     290               #   295               #   300 Gly Phe Val Tyr Phe Leu Thr Val Gln Pro Gl #u Thr Pro Glu Gly Val 305                 3 #10                 3 #15                 3 #20 Ala Ile Asn Ser Ala Gly Asp Leu Phe Tyr Th #r Ser Arg Ile Val Arg                 325   #               330   #               335 Leu Cys Lys Asp Asp Pro Lys Phe His Ser Ty #r Val Ser Leu Pro Phe             340       #           345       #           350 Gly Cys Thr Arg Ala Gly Val Glu Tyr Arg Le #u Leu Gln Ala Ala Tyr         355           #       360           #       365 Leu Ala Lys Pro Gly Asp Ser Leu Ala Gln Al #a Phe Asn Ile Thr Ser     370               #   375               #   380 Gln Asp Asp Val Leu Phe Ala Ile Phe Ser Ly #s Gly Gln Lys Gln Tyr 385                 3 #90                 3 #95                 4 #00 His His Pro Pro Asp Asp Ser Ala Leu Cys Al #a Phe Pro Ile Arg Ala                 405   #               410   #               415 Ile Asn Leu Gln Ile Lys Glu Arg Leu Gln Se #r Cys Tyr Gln Gly Glu             420       #           425       #           430 Gly Asn Leu Glu Leu Asn Trp Leu Leu Gly Ly #s Asp Val Gln Cys Thr         435           #       440           #       445 Lys Ala Pro Val Pro Ile Asp Asp Asn Phe Cy #s Gly Leu Asp Ile Asn     450               #   455               #   460 Gln Pro Leu Gly Gly Ser Thr Pro Val Glu Gl #y Leu Thr Leu Tyr Thr 465                 4 #70                 4 #75                 4 #80 Thr Ser Arg Asp Arg Met Thr Ser Val Ala Se #r Tyr Val Tyr Asn Gly                 485   #               490   #               495 Tyr Ser Val Val Phe Val Gly Thr Lys Ser Gl #y Lys Leu Lys Lys Val             500       #           505       #           510 Arg Val Tyr Glu Phe Arg Cys Ser Asn Ala Il #e His Leu Leu Ser Lys         515           #       520           #       525 Glu Ser Leu Leu Glu Gly Ser Tyr Trp Trp Ar #g Phe Asn Tyr Arg Gln     530               #   535               #   540 Leu Tyr Phe Leu Gly Glu Gln Arg 545                 5 #50 <210> SEQ ID NO 171 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 171 tggaataccg cctcctgcag             #                   #                   # 20 <210> SEQ ID NO 172 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 172 cttctgccct ttggagaaga tggc           #                   #                24 <210> SEQ ID NO 173 <211> LENGTH: 43 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 173 ggactcactg gcccaggcct tcaatatcac cagccaggac gat     #                   # 43 <210> SEQ ID NO 174 <211> LENGTH: 3106 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (1683) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 174 aggctcccgc gcgcggctga gtgcggactg gagtgggaac ccgggtcccc gc #gcttagag     60 aacacgcgat gaccacgtgg agcctccggc ggaggccggc ccgcacgctg gg #actcctgc    120 tgctggtcgt cttgggcttc ctggtgctcc gcaggctgga ctggagcacc ct #ggtccctc    180 tgcggctccg ccatcgacag ctggggctgc aggccaaggg ctggaacttc at #gctggagg    240 attccacctt ctggatcttc gggggctcca tccactattt ccgtgtgccc ag #ggagtact    300 ggagggaccg cctgctgaag atgaaggcct gtggcttgaa caccctcacc ac #ctatgttc    360 cgtggaacct gcatgagcca gaaagaggca aatttgactt ctctgggaac ct #ggacctgg    420 aggccttcgt cctgatggcc gcagagatcg ggctgtgggt gattctgcgt cc #aggcccct    480 acatctgcag tgagatggac ctcgggggct tgcccagctg gctactccaa ga #ccctggca    540 tgaggctgag gacaacttac aagggcttca ccgaagcagt ggacctttat tt #tgaccacc    600 tgatgtccag ggtggtgcca ctccagtaca agcgtggggg acctatcatt gc #cgtgcagg    660 tggagaatga atatggttcc tataataaag accccgcata catgccctac gt #caagaagg    720 cactggagga ccgtggcatt gtggaactgc tcctgacttc agacaacaag ga #tgggctga    780 gcaaggggat tgtccaggga gtcttggcca ccatcaactt gcagtcaaca ca #cgagctgc    840 agctactgac cacctttctc ttcaacgtcc aggggactca gcccaagatg gt #gatggagt    900 actggacggg gtggtttgac tcgtggggag gccctcacaa tatcttggat tc #ttctgagg    960 ttttgaaaac cgtgtctgcc attgtggacg ccggctcctc catcaacctc ta #catgttcc   1020 acggaggcac caactttggc ttcatgaatg gagccatgca cttccatgac ta #caagtcag   1080 atgtcaccag ctatgactat gatgctgtgc tgacagaagc cggcgattac ac #ggccaagt   1140 acatgaagct tcgagacttc ttcggctcca tctcaggcat ccctctccct cc #cccacctg   1200 accttcttcc caagatgccg tatgagccct taacgccagt cttgtacctg tc #tctgtggg   1260 acgccctcaa gtacctgggg gagccaatca agtctgaaaa gcccatcaac at #ggagaacc   1320 tgccagtcaa tgggggaaat ggacagtcct tcgggtacat tctctatgag ac #cagcatca   1380 cctcgtctgg catcctcagt ggccacgtgc atgatcgggg gcaggtgttt gt #gaacacag   1440 tatccatagg attcttggac tacaagacaa cgaagattgc tgtccccctg at #ccagggtt   1500 acaccgtgct gaggatcttg gtggagaatc gtgggcgagt caactatggg ga #gaatattg   1560 atgaccagcg caaaggctta attggaaatc tctatctgaa tgattcaccc ct #gaaaaact   1620 tcagaatcta tagcctggat atgaagaaga gcttctttca gaggttcggc ct #ggacaaat   1680 ggngttccct cccagaaaca cccacattac ctgctttctt cttgggtagc tt #gtccatca   1740 gctccacgcc ttgtgacacc tttctgaagc tggagggctg ggagaagggg gt #tgtattca   1800 tcaatggcca gaaccttgga cgttactgga acattggacc ccagaagacg ct #ttacctcc   1860 caggtccctg gttgagcagc ggaatcaacc aggtcatcgt ttttgaggag ac #gatggcgg   1920 gccctgcatt acagttcacg gaaacccccc acctgggcag gaaccagtac at #taagtgag   1980 cggtggcacc ccctcctgct ggtgccagtg ggagactgcc gcctcctctt ga #cctgaagc   2040 ctggtggctg ctgccccacc cctcactgca aaagcatctc cttaagtagc aa #cctcaggg   2100 actgggggct acagtctgcc cctgtctcag ctcaaaaccc taagcctgca gg #gaaaggtg   2160 ggatggctct gggcctggct ttgttgatga tggctttcct acagccctgc tc #ttgtgccg   2220 aggctgtcgg gctgtctcta gggtgggagc agctaatcag atcgcccagc ct #ttggccct   2280 cagaaaaagt gctgaaacgt gcccttgcac cggacgtcac agccctgcga gc #atctgctg   2340 gactcaggcg tgctctttgc tggttcctgg gaggcttggc cacatccctc at #ggccccat   2400 tttatccccg aaatcctggg tgtgtcacca gtgtagaggg tggggaaggg gt #gtctcacc   2460 tgagctgact ttgttcttcc ttcacaacct tctgagcctt ctttgggatt ct #ggaaggaa   2520 ctcggcgtga gaaacatgtg acttcccctt tcccttccca ctcgctgctt cc #cacagggt   2580 gacaggctgg gctggagaaa cagaaatcct caccctgcgt cttcccaagt ta #gcaggtgt   2640 ctctggtgtt cagtgaggag gacatgtgag tcctggcaga agccatggcc ca #tgtctgca   2700 catccaggga ggaggacaga aggcccagct cacatgtgag tcctggcaga ag #ccatggcc   2760 catgtctgca catccaggga ggaggacaga aggcccagct cacatgtgag tc #ctggcaga   2820 agccatggcc catgtctgca catccaggga ggaggacaga aggcccagct ca #catgtgag   2880 tcctggcaga agccatggcc catgtctgca catccaggga ggaggacaga ag #gcccagct   2940 cagtggcccc cgctccccac cccccacgcc cgaacagcag gggcagagca gc #cctccttc   3000 gaagtgtgtc caagtccgca tttgagcctt gttctggggc ccagcccaac ac #ctggcttg   3060 ggctcactgt cctgagttgc agtaaagcta taaccttgaa tcacaa    #               3106 <210> SEQ ID NO 175 <211> LENGTH: 636 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: MOD_RES <222> LOCATION: (539) <223> OTHER INFORMATION: Any amino acid <400> SEQUENCE: 175 Met Thr Thr Trp Ser Leu Arg Arg Arg Pro Al #a Arg Thr Leu Gly Leu   1               5  #                 10  #                 15 Leu Leu Leu Val Val Leu Gly Phe Leu Val Le #u Arg Arg Leu Asp Trp              20      #             25      #             30 Ser Thr Leu Val Pro Leu Arg Leu Arg His Ar #g Gln Leu Gly Leu Gln          35          #         40          #         45 Ala Lys Gly Trp Asn Phe Met Leu Glu Asp Se #r Thr Phe Trp Ile Phe      50              #     55              #     60 Gly Gly Ser Ile His Tyr Phe Arg Val Pro Ar #g Glu Tyr Trp Arg Asp  65                  # 70                  # 75                  # 80 Arg Leu Leu Lys Met Lys Ala Cys Gly Leu As #n Thr Leu Thr Thr Tyr                  85  #                 90  #                 95 Val Pro Trp Asn Leu His Glu Pro Glu Arg Gl #y Lys Phe Asp Phe Ser             100       #           105       #           110 Gly Asn Leu Asp Leu Glu Ala Phe Val Leu Me #t Ala Ala Glu Ile Gly         115           #       120           #       125 Leu Trp Val Ile Leu Arg Pro Gly Pro Tyr Il #e Cys Ser Glu Met Asp     130               #   135               #   140 Leu Gly Gly Leu Pro Ser Trp Leu Leu Gln As #p Pro Gly Met Arg Leu 145                 1 #50                 1 #55                 1 #60 Arg Thr Thr Tyr Lys Gly Phe Thr Glu Ala Va #l Asp Leu Tyr Phe Asp                 165   #               170   #               175 His Leu Met Ser Arg Val Val Pro Leu Gln Ty #r Lys Arg Gly Gly Pro             180       #           185       #           190 Ile Ile Ala Val Gln Val Glu Asn Glu Tyr Gl #y Ser Tyr Asn Lys Asp         195           #       200           #       205 Pro Ala Tyr Met Pro Tyr Val Lys Lys Ala Le #u Glu Asp Arg Gly Ile     210               #   215               #   220 Val Glu Leu Leu Leu Thr Ser Asp Asn Lys As #p Gly Leu Ser Lys Gly 225                 2 #30                 2 #35                 2 #40 Ile Val Gln Gly Val Leu Ala Thr Ile Asn Le #u Gln Ser Thr His Glu                 245   #               250   #               255 Leu Gln Leu Leu Thr Thr Phe Leu Phe Asn Va #l Gln Gly Thr Gln Pro             260       #           265       #           270 Lys Met Val Met Glu Tyr Trp Thr Gly Trp Ph #e Asp Ser Trp Gly Gly         275           #       280           #       285 Pro His Asn Ile Leu Asp Ser Ser Glu Val Le #u Lys Thr Val Ser Ala     290               #   295               #   300 Ile Val Asp Ala Gly Ser Ser Ile Asn Leu Ty #r Met Phe His Gly Gly 305                 3 #10                 3 #15                 3 #20 Thr Asn Phe Gly Phe Met Asn Gly Ala Met Hi #s Phe His Asp Tyr Lys                 325   #               330   #               335 Ser Asp Val Thr Ser Tyr Asp Tyr Asp Ala Va #l Leu Thr Glu Ala Gly             340       #           345       #           350 Asp Tyr Thr Ala Lys Tyr Met Lys Leu Arg As #p Phe Phe Gly Ser Ile         355           #       360           #       365 Ser Gly Ile Pro Leu Pro Pro Pro Pro Asp Le #u Leu Pro Lys Met Pro     370               #   375               #   380 Tyr Glu Pro Leu Thr Pro Val Leu Tyr Leu Se #r Leu Trp Asp Ala Leu 385                 3 #90                 3 #95                 4 #00 Lys Tyr Leu Gly Glu Pro Ile Lys Ser Glu Ly #s Pro Ile Asn Met Glu                 405   #               410   #               415 Asn Leu Pro Val Asn Gly Gly Asn Gly Gln Se #r Phe Gly Tyr Ile Leu             420       #           425       #           430 Tyr Glu Thr Ser Ile Thr Ser Ser Gly Ile Le #u Ser Gly His Val His         435           #       440           #       445 Asp Arg Gly Gln Val Phe Val Asn Thr Val Se #r Ile Gly Phe Leu Asp     450               #   455               #   460 Tyr Lys Thr Thr Lys Ile Ala Val Pro Leu Il #e Gln Gly Tyr Thr Val 465                 4 #70                 4 #75                 4 #80 Leu Arg Ile Leu Val Glu Asn Arg Gly Arg Va #l Asn Tyr Gly Glu Asn                 485   #               490   #               495 Ile Asp Asp Gln Arg Lys Gly Leu Ile Gly As #n Leu Tyr Leu Asn Asp             500       #           505       #           510 Ser Pro Leu Lys Asn Phe Arg Ile Tyr Ser Le #u Asp Met Lys Lys Ser         515           #       520           #       525 Phe Phe Gln Arg Phe Gly Leu Asp Lys Trp Xa #a Ser Leu Pro Glu Thr     530               #   535               #   540 Pro Thr Leu Pro Ala Phe Phe Leu Gly Ser Le #u Ser Ile Ser Ser Thr 545                 5 #50                 5 #55                 5 #60 Pro Cys Asp Thr Phe Leu Lys Leu Glu Gly Tr #p Glu Lys Gly Val Val                 565   #               570   #               575 Phe Ile Asn Gly Gln Asn Leu Gly Arg Tyr Tr #p Asn Ile Gly Pro Gln             580       #           585       #           590 Lys Thr Leu Tyr Leu Pro Gly Pro Trp Leu Se #r Ser Gly Ile Asn Gln         595           #       600           #       605 Val Ile Val Phe Glu Glu Thr Met Ala Gly Pr #o Ala Leu Gln Phe Thr     610               #   615               #   620 Glu Thr Pro His Leu Gly Arg Asn Gln Tyr Il #e Lys 625                 6 #30                 6 #35 <210> SEQ ID NO 176 <211> LENGTH: 2505 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 176 ggggacgcgg agctgagagg ctccgggcta gctaggtgta ggggtggacg gg #tcccagga     60 ccctggtgag ggttctctac ttggccttcg gtgggggtca agacgcaggc ac #ctacgcca    120 aaggggagca aagccgggct cggcccgagg cccccaggac ctccatctcc ca #atgttgga    180 ggaatccgac acgtgacggt ctgtccgccg tctcagacta gaggagcgct gt #aaacgcca    240 tggctcccaa gaagctgtcc tgccttcgtt ccctgctgct gccgctcagc ct #gacgctac    300 tgctgcccca ggcagacact cggtcgttcg tagtggatag gggtcatgac cg #gtttctcc    360 tagacggggc cccgttccgc tatgtgtctg gcagcctgca ctactttcgg gt #accgcggg    420 tgctttgggc cgaccggctt ttgaagatgc gatggagcgg cctcaacgcc at #acagtttt    480 atgtgccctg gaactaccac gagccacagc ctggggtcta taactttaat gg #cagccggg    540 acctcattgc ctttctgaat gaggcagctc tagcgaacct gttggtcata ct #gagaccag    600 gaccttacat ctgtgcagag tgggagatgg ggggtctccc atcctggttg ct #tcgaaaac    660 ctgaaattca tctaagaacc tcagatccag acttccttgc cgcagtggac tc #ctggttca    720 aggtcttgct gcccaagata tatccatggc tttatcacaa tgggggcaac at #cattagca    780 ttcaggtgga gaatgaatat ggtagctaca gagcctgtga cttcagctac at #gaggcact    840 tggctgggct cttccgtgca ctgctaggag aaaagatctt gctcttcacc ac #agatgggc    900 ctgaaggact caagtgtggc tccctccggg gactctatac cactgtagat tt #tggcccag    960 ctgacaacat gaccaaaatc tttaccctgc ttcggaagta tgaaccccat gg #gccattgg   1020 taaactctga gtactacaca ggctggctgg attactgggg ccagaatcac tc #cacacggt   1080 ctgtgtcagc tgtaaccaaa ggactagaga acatgctcaa gttgggagcc ag #tgtgaaca   1140 tgtacatgtt ccatggaggt accaactttg gatattggaa tggtgccgat aa #gaagggac   1200 gcttccttcc gattactacc agctatgact atgatgcacc tatatctgaa gc #aggggacc   1260 ccacacctaa gctttttgct cttcgagatg tcatcagcaa gttccaggaa gt #tcctttgg   1320 gacctttacc tcccccgagc cccaagatga tgcttggacc tgtgactctg ca #cctggttg   1380 ggcatttact ggctttccta gacttgcttt gcccccgtgg gcccattcat tc #aatcttgc   1440 caatgacctt tgaggctgtc aagcaggacc atggcttcat gttgtaccga ac #ctatatga   1500 cccataccat ttttgagcca acaccattct gggtgccaaa taatggagtc ca #tgaccgtg   1560 cctatgtgat ggtggatggg gtgttccagg gtgttgtgga gcgaaatatg ag #agacaaac   1620 tatttttgac ggggaaactg gggtccaaac tggatatctt ggtggagaac at #ggggaggc   1680 tcagctttgg gtctaacagc agtgacttca agggcctgtt gaagccacca at #tctggggc   1740 aaacaatcct tacccagtgg atgatgttcc ctctgaaaat tgataacctt gt #gaagtggt   1800 ggtttcccct ccagttgcca aaatggccat atcctcaagc tccttctggc cc #cacattct   1860 actccaaaac atttccaatt ttaggctcag ttggggacac atttctatat ct #acctggat   1920 ggaccaaggg ccaagtctgg atcaatgggt ttaacttggg ccggtactgg ac #aaagcagg   1980 ggccacaaca gaccctctac gtgccaagat tcctgctgtt tcctagggga gc #cctcaaca   2040 aaattacatt gctggaacta gaagatgtac ctctccagcc ccaagtccaa tt #tttggata   2100 agcctatcct caatagcact agtactttgc acaggacaca tatcaattcc ct #ttcagctg   2160 atacactgag tgcctctgaa ccaatggagt taagtgggca ctgaaaggta gg #ccgggcat   2220 ggtggctcat gcctgtaatc ccagcacttt gggaggctga gacgggtgga tt #acctgagg   2280 tcaggacttc aagaccagcc tggccaacat ggtgaaaccc cgtctccact aa #aaatacaa   2340 aaattagccg ggcgtgatgg tgggcacctc taatcccagc tacttgggag gc #tgagggca   2400 ggagaattgc ttgaatccag gaggcagagg ttgcagtgag tggaggttgt ac #cactgcac   2460 tccagcctgg ctgacagtga gacactccat ctcaaaaaaa aaaaa    #                2505 <210> SEQ ID NO 177 <211> LENGTH: 654 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 177 Met Ala Pro Lys Lys Leu Ser Cys Leu Arg Se #r Leu Leu Leu Pro Leu   1               5  #                 10  #                 15 Ser Leu Thr Leu Leu Leu Pro Gln Ala Asp Th #r Arg Ser Phe Val Val              20      #             25      #             30 Asp Arg Gly His Asp Arg Phe Leu Leu Asp Gl #y Ala Pro Phe Arg Tyr          35          #         40          #         45 Val Ser Gly Ser Leu His Tyr Phe Arg Val Pr #o Arg Val Leu Trp Ala      50              #     55              #     60 Asp Arg Leu Leu Lys Met Arg Trp Ser Gly Le #u Asn Ala Ile Gln Phe  65                  # 70                  # 75                  # 80 Tyr Val Pro Trp Asn Tyr His Glu Pro Gln Pr #o Gly Val Tyr Asn Phe                  85  #                 90  #                 95 Asn Gly Ser Arg Asp Leu Ile Ala Phe Leu As #n Glu Ala Ala Leu Ala             100       #           105       #           110 Asn Leu Leu Val Ile Leu Arg Pro Gly Pro Ty #r Ile Cys Ala Glu Trp         115           #       120           #       125 Glu Met Gly Gly Leu Pro Ser Trp Leu Leu Ar #g Lys Pro Glu Ile His     130               #   135               #   140 Leu Arg Thr Ser Asp Pro Asp Phe Leu Ala Al #a Val Asp Ser Trp Phe 145                 1 #50                 1 #55                 1 #60 Lys Val Leu Leu Pro Lys Ile Tyr Pro Trp Le #u Tyr His Asn Gly Gly                 165   #               170   #               175 Asn Ile Ile Ser Ile Gln Val Glu Asn Glu Ty #r Gly Ser Tyr Arg Ala             180       #           185       #           190 Cys Asp Phe Ser Tyr Met Arg His Leu Ala Gl #y Leu Phe Arg Ala Leu         195           #       200           #       205 Leu Gly Glu Lys Ile Leu Leu Phe Thr Thr As #p Gly Pro Glu Gly Leu     210               #   215               #   220 Lys Cys Gly Ser Leu Arg Gly Leu Tyr Thr Th #r Val Asp Phe Gly Pro 225                 2 #30                 2 #35                 2 #40 Ala Asp Asn Met Thr Lys Ile Phe Thr Leu Le #u Arg Lys Tyr Glu Pro                 245   #               250   #               255 His Gly Pro Leu Val Asn Ser Glu Tyr Tyr Th #r Gly Trp Leu Asp Tyr             260       #           265       #           270 Trp Gly Gln Asn His Ser Thr Arg Ser Val Se #r Ala Val Thr Lys Gly         275           #       280           #       285 Leu Glu Asn Met Leu Lys Leu Gly Ala Ser Va #l Asn Met Tyr Met Phe     290               #   295               #   300 His Gly Gly Thr Asn Phe Gly Tyr Trp Asn Gl #y Ala Asp Lys Lys Gly 305                 3 #10                 3 #15                 3 #20 Arg Phe Leu Pro Ile Thr Thr Ser Tyr Asp Ty #r Asp Ala Pro Ile Ser                 325   #               330   #               335 Glu Ala Gly Asp Pro Thr Pro Lys Leu Phe Al #a Leu Arg Asp Val Ile             340       #           345       #           350 Ser Lys Phe Gln Glu Val Pro Leu Gly Pro Le #u Pro Pro Pro Ser Pro         355           #       360           #       365 Lys Met Met Leu Gly Pro Val Thr Leu His Le #u Val Gly His Leu Leu     370               #   375               #   380 Ala Phe Leu Asp Leu Leu Cys Pro Arg Gly Pr #o Ile His Ser Ile Leu 385                 3 #90                 3 #95                 4 #00 Pro Met Thr Phe Glu Ala Val Lys Gln Asp Hi #s Gly Phe Met Leu Tyr                 405   #               410   #               415 Arg Thr Tyr Met Thr His Thr Ile Phe Glu Pr #o Thr Pro Phe Trp Val             420       #           425       #           430 Pro Asn Asn Gly Val His Asp Arg Ala Tyr Va #l Met Val Asp Gly Val         435           #       440           #       445 Phe Gln Gly Val Val Glu Arg Asn Met Arg As #p Lys Leu Phe Leu Thr     450               #   455               #   460 Gly Lys Leu Gly Ser Lys Leu Asp Ile Leu Va #l Glu Asn Met Gly Arg 465                 4 #70                 4 #75                 4 #80 Leu Ser Phe Gly Ser Asn Ser Ser Asp Phe Ly #s Gly Leu Leu Lys Pro                 485   #               490   #               495 Pro Ile Leu Gly Gln Thr Ile Leu Thr Gln Tr #p Met Met Phe Pro Leu             500       #           505       #           510 Lys Ile Asp Asn Leu Val Lys Trp Trp Phe Pr #o Leu Gln Leu Pro Lys         515           #       520           #       525 Trp Pro Tyr Pro Gln Ala Pro Ser Gly Pro Th #r Phe Tyr Ser Lys Thr     530               #   535               #   540 Phe Pro Ile Leu Gly Ser Val Gly Asp Thr Ph #e Leu Tyr Leu Pro Gly 545                 5 #50                 5 #55                 5 #60 Trp Thr Lys Gly Gln Val Trp Ile Asn Gly Ph #e Asn Leu Gly Arg Tyr                 565   #               570   #               575 Trp Thr Lys Gln Gly Pro Gln Gln Thr Leu Ty #r Val Pro Arg Phe Leu             580       #           585       #           590 Leu Phe Pro Arg Gly Ala Leu Asn Lys Ile Th #r Leu Leu Glu Leu Glu         595           #       600           #       605 Asp Val Pro Leu Gln Pro Gln Val Gln Phe Le #u Asp Lys Pro Ile Leu     610               #   615               #   620 Asn Ser Thr Ser Thr Leu His Arg Thr His Il #e Asn Ser Leu Ser Ala 625                 6 #30                 6 #35                 6 #40 Asp Thr Leu Ser Ala Ser Glu Pro Met Glu Le #u Ser Gly His                 645   #               650 <210> SEQ ID NO 178 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 178 tggctactcc aagaccctgg catg           #                   #                24 <210> SEQ ID NO 179 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 179 tggacaaatc cccttgctca gccc           #                   #                24 <210> SEQ ID NO 180 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 180 gggcttcacc gaagcagtgg acctttattt tgaccacctg atgtccaggg   #              50 <210> SEQ ID NO 181 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 181 ccagctatga ctatgatgca cc            #                   #                 22 <210> SEQ ID NO 182 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 182 tggcacccag aatggtgttg gctc           #                   #                24 <210> SEQ ID NO 183 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 183 cgagatgtca tcagcaagtt ccaggaagtt cctttgggac ctttacctcc   #              50 <210> SEQ ID NO 184 <211> LENGTH: 1947 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 184 gctttgaaca cgtctgcaag cccaaagttg agcatctgat tggttatgag gt #atttgagt     60 gcacccacaa tatggcttac atgttgaaaa agcttctcat cagttacata tc #cattattt    120 gtgtttatgg ctttatctgc ctctacactc tcttctggtt attcaggata cc #tttgaagg    180 aatattcttt cgaaaaagtc agagaagaga gcagttttag tgacattcca ga #tgtcaaaa    240 acgattttgc gttccttctt cacatggtag accagtatga ccagctatat tc #caagcgtt    300 ttggtgtgtt cttgtcagaa gttagtgaaa ataaacttag ggaaattagt tt #gaaccatg    360 agtggacatt tgaaaaactc aggcagcaca tttcacgcaa cgcccaggac aa #gcaggagt    420 tgcatctgtt catgctgtcg ggggtgcccg atgctgtctt tgacctcaca ga #cctggatg    480 tgctaaagct tgaactaatt ccagaagcta aaattcctgc taagatttct ca #aatgacta    540 acctccaaga gctccacctc tgccactgcc ctgcaaaagt tgaacagact gc #ttttagct    600 ttcttcgcga tcacttgaga tgccttcacg tgaagttcac tgatgtggct ga #aattcctg    660 cctgggtgta tttgctcaaa aaccttcgag agttgtactt aataggcaat tt #gaactctg    720 aaaacaataa gatgatagga cttgaatctc tccgagagtt gcggcacctt aa #gattctcc    780 acgtgaagag caatttgacc aaagttccct ccaacattac agatgtggct cc #acatctta    840 caaagttagt cattcataat gacggcacta aactcttggt actgaacagc ct #taagaaaa    900 tgatgaatgt cgctgagctg gaactccaga actgtgagct agagagaatc cc #acatgcta    960 ttttcagcct ctctaattta caggaactgg atttaaagtc caataacatt cg #cacaattg   1020 aggaaatcat cagtttccag catttaaaac gactgacttg tttaaaatta tg #gcataaca   1080 aaattgttac tattcctccc tctattaccc atgtcaaaaa cttggagtca ct #ttatttct   1140 ctaacaacaa gctcgaatcc ttaccagtgg cagtatttag tttacagaaa ct #cagatgct   1200 tagatgtgag ctacaacaac atttcaatga ttccaataga aataggattg ct #tcagaacc   1260 tgcagcattt gcatatcact gggaacaaag tggacattct gccaaaacaa tt #gtttaaat   1320 gcataaagtt gaggactttg aatctgggac agaactgcat cacctcactc cc #agagaaag   1380 ttggtcagct ctcccagctc actcagctgg agctgaaggg gaactgcttg ga #ccgcctgc   1440 cagcccagct gggccagtgt cggatgctca agaaaagcgg gcttgttgtg ga #agatcacc   1500 tttttgatac cctgccactc gaagtcaaag aggcattgaa tcaagacata aa #tattccct   1560 ttgcaaatgg gatttaaact aagataatat atgcacagtg atgtgcagga ac #aacttcct   1620 agattgcaag tgctcacgta caagttatta caagataatg cattttagga gt #agatacat   1680 cttttaaaat aaaacagaga ggatgcatag aaggctgata gaagacataa ct #gaatgttc   1740 aatgtttgta gggttttaag tcattcattt ccaaatcatt tttttttttc tt #ttggggaa   1800 agggaaggaa aaattataat cactaatctt ggttcttttt aaattgtttg ta #acttggat   1860 gctgccgcta ctgaatgttt acaaattgct tgcctgctaa agtaaatgat ta #aattgaca   1920 ttttcttact aaaaaaaaaa aaaaaaa           #                   #           1947 <210> SEQ ID NO 185 <211> LENGTH: 501 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 185 Met Ala Tyr Met Leu Lys Lys Leu Leu Ile Se #r Tyr Ile Ser Ile Ile   1               5  #                 10  #                 15 Cys Val Tyr Gly Phe Ile Cys Leu Tyr Thr Le #u Phe Trp Leu Phe Arg              20      #             25      #             30 Ile Pro Leu Lys Glu Tyr Ser Phe Glu Lys Va #l Arg Glu Glu Ser Ser          35          #         40          #         45 Phe Ser Asp Ile Pro Asp Val Lys Asn Asp Ph #e Ala Phe Leu Leu His      50              #     55              #     60 Met Val Asp Gln Tyr Asp Gln Leu Tyr Ser Ly #s Arg Phe Gly Val Phe  65                  # 70                  # 75                  # 80 Leu Ser Glu Val Ser Glu Asn Lys Leu Arg Gl #u Ile Ser Leu Asn His                  85  #                 90  #                 95 Glu Trp Thr Phe Glu Lys Leu Arg Gln His Il #e Ser Arg Asn Ala Gln             100       #           105       #           110 Asp Lys Gln Glu Leu His Leu Phe Met Leu Se #r Gly Val Pro Asp Ala         115           #       120           #       125 Val Phe Asp Leu Thr Asp Leu Asp Val Leu Ly #s Leu Glu Leu Ile Pro     130               #   135               #   140 Glu Ala Lys Ile Pro Ala Lys Ile Ser Gln Me #t Thr Asn Leu Gln Glu 145                 1 #50                 1 #55                 1 #60 Leu His Leu Cys His Cys Pro Ala Lys Val Gl #u Gln Thr Ala Phe Ser                 165   #               170   #               175 Phe Leu Arg Asp His Leu Arg Cys Leu His Va #l Lys Phe Thr Asp Val             180       #           185       #           190 Ala Glu Ile Pro Ala Trp Val Tyr Leu Leu Ly #s Asn Leu Arg Glu Leu         195           #       200           #       205 Tyr Leu Ile Gly Asn Leu Asn Ser Glu Asn As #n Lys Met Ile Gly Leu     210               #   215               #   220 Glu Ser Leu Arg Glu Leu Arg His Leu Lys Il #e Leu His Val Lys Ser 225                 2 #30                 2 #35                 2 #40 Asn Leu Thr Lys Val Pro Ser Asn Ile Thr As #p Val Ala Pro His Leu                 245   #               250   #               255 Thr Lys Leu Val Ile His Asn Asp Gly Thr Ly #s Leu Leu Val Leu Asn             260       #           265       #           270 Ser Leu Lys Lys Met Met Asn Val Ala Glu Le #u Glu Leu Gln Asn Cys         275           #       280           #       285 Glu Leu Glu Arg Ile Pro His Ala Ile Phe Se #r Leu Ser Asn Leu Gln     290               #   295               #   300 Glu Leu Asp Leu Lys Ser Asn Asn Ile Arg Th #r Ile Glu Glu Ile Ile 305                 3 #10                 3 #15                 3 #20 Ser Phe Gln His Leu Lys Arg Leu Thr Cys Le #u Lys Leu Trp His Asn                 325   #               330   #               335 Lys Ile Val Thr Ile Pro Pro Ser Ile Thr Hi #s Val Lys Asn Leu Glu             340       #           345       #           350 Ser Leu Tyr Phe Ser Asn Asn Lys Leu Glu Se #r Leu Pro Val Ala Val         355           #       360           #       365 Phe Ser Leu Gln Lys Leu Arg Cys Leu Asp Va #l Ser Tyr Asn Asn Ile     370               #   375               #   380 Ser Met Ile Pro Ile Glu Ile Gly Leu Leu Gl #n Asn Leu Gln His Leu 385                 3 #90                 3 #95                 4 #00 His Ile Thr Gly Asn Lys Val Asp Ile Leu Pr #o Lys Gln Leu Phe Lys                 405   #               410   #               415 Cys Ile Lys Leu Arg Thr Leu Asn Leu Gly Gl #n Asn Cys Ile Thr Ser             420       #           425       #           430 Leu Pro Glu Lys Val Gly Gln Leu Ser Gln Le #u Thr Gln Leu Glu Leu         435           #       440           #       445 Lys Gly Asn Cys Leu Asp Arg Leu Pro Ala Gl #n Leu Gly Gln Cys Arg     450               #   455               #   460 Met Leu Lys Lys Ser Gly Leu Val Val Glu As #p His Leu Phe Asp Thr 465                 4 #70                 4 #75                 4 #80 Leu Pro Leu Glu Val Lys Glu Ala Leu Asn Gl #n Asp Ile Asn Ile Pro                 485   #               490   #               495 Phe Ala Asn Gly Ile             500 <210> SEQ ID NO 186 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 186 cctccctcta ttacccatgt c            #                   #                   #21 <210> SEQ ID NO 187 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 187 gaccaacttt ctctgggagt gagg           #                   #                24 <210> SEQ ID NO 188 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 188 gtcactttat ttctctaaca acaagctcga atccttacca gtggcag    #                47 <210> SEQ ID NO 189 <211> LENGTH: 2917 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 189 cccacgcgtc cggccttctc tctggacttt gcatttccat tccttttcat tg #acaaactg     60 acttttttta tttctttttt tccatctctg ggccagcttg ggatcctagg cc #gccctggg    120 aagacatttg tgttttacac acataaggat ctgtgtttgg ggtttcttct tc #ctcccctg    180 acattggcat tgcttagtgg ttgtgtgggg agggagacca cgtgggctca gt #gcttgctt    240 gcacttatct gcctaggtac atcgaagtct tttgacctcc atacagtgat ta #tgcctgtc    300 atcgctggtg gtatcctggc ggccttgctc ctgctgatag ttgtcgtgct ct #gtctttac    360 ttcaaaatac acaacgcgct aaaagctgca aaggaacctg aagctgtggc tg #taaaaaat    420 cacaacccag acaaggtgtg gtgggccaag aacagccagg ccaaaaccat tg #ccacggag    480 tcttgtcctg ccctgcagtg ctgtgaagga tatagaatgt gtgccagttt tg #attccctg    540 ccaccttgct gttgcgacat aaatgagggc ctctgagtta ggaaaggctc cc #ttctcaaa    600 gcagagccct gaagacttca atgatgtcaa tgaggccacc tgtttgtgat gt #gcaggcac    660 agaagaaagg cacagctccc catcagtttc atggaaaata actcagtgcc tg #ctgggaac    720 cagctgctgg agatccctac agagagcttc cactgggggc aacccttcca gg #aaggagtt    780 ggggagagag aaccctcact gtggggaatg ctgataaacc agtcacacag ct #gctctatt    840 ctcacacaaa tctacccctt gcgtggctgg aactgacgtt tccctggagg tg #tccagaaa    900 gctgatgtaa cacagagcct ataaaagctg tcggtcctta aggctgccca gc #gccttgcc    960 aaaatggagc ttgtaagaag gctcatgcca ttgaccctct taattctctc ct #gtttggcg   1020 gagctgacaa tggcggaggc tgaaggcaat gcaagctgca cagtcagtct ag #ggggtgcc   1080 aatatggcag agacccacaa agccatgatc ctgcaactca atcccagtga ga #actgcacc   1140 tggacaatag aaagaccaga aaacaaaagc atcagaatta tcttttccta tg #tccagctt   1200 gatccagatg gaagctgtga aagtgaaaac attaaagtct ttgacggaac ct #ccagcaat   1260 gggcctctgc tagggcaagt ctgcagtaaa aacgactatg ttcctgtatt tg #aatcatca   1320 tccagtacat tgacgtttca aatagttact gactcagcaa gaattcaaag aa #ctgtcttt   1380 gtcttctact acttcttctc tcctaacatc tctattccaa actgtggcgg tt #acctggat   1440 accttggaag gatccttcac cagccccaat tacccaaagc cgcatcctga gc #tggcttat   1500 tgtgtgtggc acatacaagt ggagaaagat tacaagataa aactaaactt ca #aagagatt   1560 ttcctagaaa tagacaaaca gtgcaaattt gattttcttg ccatctatga tg #gcccctcc   1620 accaactctg gcctgattgg acaagtctgt ggccgtgtga ctcccacctt cg #aatcgtca   1680 tcaaactctc tgactgtcgt gttgtctaca gattatgcca attcttaccg gg #gattttct   1740 gcttcctaca cctcaattta tgcagaaaac atcaacacta catctttaac tt #gctcttct   1800 gacaggatga gagttattat aagcaaatcc tacctagagg cttttaactc ta #atgggaat   1860 aacttgcaac taaaagaccc aacttgcaga ccaaaattat caaatgttgt gg #aattttct   1920 gtccctctta atggatgtgg tacaatcaga aaggtagaag atcagtcaat ta #cttacacc   1980 aatataatca ccttttctgc atcctcaact tctgaagtga tcacccgtca ga #aacaactc   2040 cagattattg tgaagtgtga aatgggacat aattctacag tggagataat at #acataaca   2100 gaagatgatg taatacaaag tcaaaatgca ctgggcaaat ataacaccag ca #tggctctt   2160 tttgaatcca attcatttga aaagactata cttgaatcac catattatgt gg #atttgaac   2220 caaactcttt ttgttcaagt tagtctgcac acctcagatc caaatttggt gg #tgtttctt   2280 gatacctgta gagcctctcc cacctctgac tttgcatctc caacctacga cc #taatcaag   2340 agtggatgta gtcgagatga aacttgtaag gtgtatccct tatttggaca ct #atgggaga   2400 ttccagttta atgcctttaa attcttgaga agtatgagct ctgtgtatct gc #agtgtaaa   2460 gttttgatat gtgatagcag tgaccaccag tctcgctgca atcaaggttg tg #tctccaga   2520 agcaaacgag acatttcttc atataaatgg aaaacagatt ccatcatagg ac #ccattcgt   2580 ctgaaaaggg atcgaagtgc aagtggcaat tcaggatttc agcatgaaac ac #atgcggaa   2640 gaaactccaa accagccttt caacagtgtg catctgtttt ccttcatggt tc #tagctctg   2700 aatgtggtga ctgtagcgac aatcacagtg aggcattttg taaatcaacg gg #cagactac   2760 aaataccaga agctgcagaa ctattaacta acaggtccaa ccctaagtga ga #catgtttc   2820 tccaggatgc caaaggaaat gctacctcgt ggctacacat attatgaata aa #tgaggaag   2880 ggcctgaaag tgacacacag gcctgcatgt aaaaaaa       #                   #    2917 <210> SEQ ID NO 190 <211> LENGTH: 607 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 190 Met Glu Leu Val Arg Arg Leu Met Pro Leu Th #r Leu Leu Ile Leu Ser   1               5  #                 10  #                 15 Cys Leu Ala Glu Leu Thr Met Ala Glu Ala Gl #u Gly Asn Ala Ser Cys              20      #             25      #             30 Thr Val Ser Leu Gly Gly Ala Asn Met Ala Gl #u Thr His Lys Ala Met          35          #         40          #         45 Ile Leu Gln Leu Asn Pro Ser Glu Asn Cys Th #r Trp Thr Ile Glu Arg      50              #     55              #     60 Pro Glu Asn Lys Ser Ile Arg Ile Ile Phe Se #r Tyr Val Gln Leu Asp  65                  # 70                  # 75                  # 80 Pro Asp Gly Ser Cys Glu Ser Glu Asn Ile Ly #s Val Phe Asp Gly Thr                  85  #                 90  #                 95 Ser Ser Asn Gly Pro Leu Leu Gly Gln Val Cy #s Ser Lys Asn Asp Tyr             100       #           105       #           110 Val Pro Val Phe Glu Ser Ser Ser Ser Thr Le #u Thr Phe Gln Ile Val         115           #       120           #       125 Thr Asp Ser Ala Arg Ile Gln Arg Thr Val Ph #e Val Phe Tyr Tyr Phe     130               #   135               #   140 Phe Ser Pro Asn Ile Ser Ile Pro Asn Cys Gl #y Gly Tyr Leu Asp Thr 145                 1 #50                 1 #55                 1 #60 Leu Glu Gly Ser Phe Thr Ser Pro Asn Tyr Pr #o Lys Pro His Pro Glu                 165   #               170   #               175 Leu Ala Tyr Cys Val Trp His Ile Gln Val Gl #u Lys Asp Tyr Lys Ile             180       #           185       #           190 Lys Leu Asn Phe Lys Glu Ile Phe Leu Glu Il #e Asp Lys Gln Cys Lys         195           #       200           #       205 Phe Asp Phe Leu Ala Ile Tyr Asp Gly Pro Se #r Thr Asn Ser Gly Leu     210               #   215               #   220 Ile Gly Gln Val Cys Gly Arg Val Thr Pro Th #r Phe Glu Ser Ser Ser 225                 2 #30                 2 #35                 2 #40 Asn Ser Leu Thr Val Val Leu Ser Thr Asp Ty #r Ala Asn Ser Tyr Arg                 245   #               250   #               255 Gly Phe Ser Ala Ser Tyr Thr Ser Ile Tyr Al #a Glu Asn Ile Asn Thr             260       #           265       #           270 Thr Ser Leu Thr Cys Ser Ser Asp Arg Met Ar #g Val Ile Ile Ser Lys         275           #       280           #       285 Ser Tyr Leu Glu Ala Phe Asn Ser Asn Gly As #n Asn Leu Gln Leu Lys     290               #   295               #   300 Asp Pro Thr Cys Arg Pro Lys Leu Ser Asn Va #l Val Glu Phe Ser Val 305                 3 #10                 3 #15                 3 #20 Pro Leu Asn Gly Cys Gly Thr Ile Arg Lys Va #l Glu Asp Gln Ser Ile                 325   #               330   #               335 Thr Tyr Thr Asn Ile Ile Thr Phe Ser Ala Se #r Ser Thr Ser Glu Val             340       #           345       #           350 Ile Thr Arg Gln Lys Gln Leu Gln Ile Ile Va #l Lys Cys Glu Met Gly         355           #       360           #       365 His Asn Ser Thr Val Glu Ile Ile Tyr Ile Th #r Glu Asp Asp Val Ile     370               #   375               #   380 Gln Ser Gln Asn Ala Leu Gly Lys Tyr Asn Th #r Ser Met Ala Leu Phe 385                 3 #90                 3 #95                 4 #00 Glu Ser Asn Ser Phe Glu Lys Thr Ile Leu Gl #u Ser Pro Tyr Tyr Val                 405   #               410   #               415 Asp Leu Asn Gln Thr Leu Phe Val Gln Val Se #r Leu His Thr Ser Asp             420       #           425       #           430 Pro Asn Leu Val Val Phe Leu Asp Thr Cys Ar #g Ala Ser Pro Thr Ser         435           #       440           #       445 Asp Phe Ala Ser Pro Thr Tyr Asp Leu Ile Ly #s Ser Gly Cys Ser Arg     450               #   455               #   460 Asp Glu Thr Cys Lys Val Tyr Pro Leu Phe Gl #y His Tyr Gly Arg Phe 465                 4 #70                 4 #75                 4 #80 Gln Phe Asn Ala Phe Lys Phe Leu Arg Ser Me #t Ser Ser Val Tyr Leu                 485   #               490   #               495 Gln Cys Lys Val Leu Ile Cys Asp Ser Ser As #p His Gln Ser Arg Cys             500       #           505       #           510 Asn Gln Gly Cys Val Ser Arg Ser Lys Arg As #p Ile Ser Ser Tyr Lys         515           #       520           #       525 Trp Lys Thr Asp Ser Ile Ile Gly Pro Ile Ar #g Leu Lys Arg Asp Arg     530               #   535               #   540 Ser Ala Ser Gly Asn Ser Gly Phe Gln His Gl #u Thr His Ala Glu Glu 545                 5 #50                 5 #55                 5 #60 Thr Pro Asn Gln Pro Phe Asn Ser Val His Le #u Phe Ser Phe Met Val                 565   #               570   #               575 Leu Ala Leu Asn Val Val Thr Val Ala Thr Il #e Thr Val Arg His Phe             580       #           585       #           590 Val Asn Gln Arg Ala Asp Tyr Lys Tyr Gln Ly #s Leu Gln Asn Tyr         595           #       600           #       605 <210> SEQ ID NO 191 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 191 tctctattcc aaactgtggc g            #                   #                   #21 <210> SEQ ID NO 192 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 192 tttgatgacg attcgaaggt gg            #                   #                 22 <210> SEQ ID NO 193 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 193 ggaaggatcc ttcaccagcc ccaattaccc aaagccgcat cctgagc    #                47 <210> SEQ ID NO 194 <211> LENGTH: 2362 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 194 gacggaagaa cagcgctccc gaggccgcgg gagcctgcag agaggacagc cg #gcctgcgc     60 cgggacatgc ggccccagga gctccccagg ctcgcgttcc cgttgctgct gt #tgctgttg    120 ctgctgctgc cgccgccgcc gtgccctgcc cacagcgcca cgcgcttcga cc #ccacctgg    180 gagtccctgg acgcccgcca gctgcccgcg tggtttgacc aggccaagtt cg #gcatcttc    240 atccactggg gagtgttttc cgtgcccagc ttcggtagcg agtggttctg gt #ggtattgg    300 caaaaggaaa agataccgaa gtatgtggaa tttatgaaag ataattaccc tc #ctagtttc    360 aaatatgaag attttggacc actatttaca gcaaaatttt ttaatgccaa cc #agtgggca    420 gatatttttc aggcctctgg tgccaaatac attgtcttaa cttccaaaca tc #atgaaggc    480 tttaccttgt gggggtcaga atattcgtgg aactggaatg ccatagatga gg #ggcccaag    540 agggacattg tcaaggaact tgaggtagcc attaggaaca gaactgacct gc #gttttgga    600 ctgtactatt ccctttttga atggtttcat ccgctcttcc ttgaggatga at #ccagttca    660 ttccataagc ggcaatttcc agtttctaag acattgccag agctctatga gt #tagtgaac    720 aactatcagc ctgaggttct gtggtcggat ggtgacggag gagcaccgga tc #aatactgg    780 aacagcacag gcttcttggc ctggttatat aatgaaagcc cagttcgggg ca #cagtagtc    840 accaatgatc gttggggagc tggtagcatc tgtaagcatg gtggcttcta ta #cctgcagt    900 gatcgttata acccaggaca tcttttgcca cataaatggg aaaactgcat ga #caatagac    960 aaactgtcct ggggctatag gagggaagct ggaatctctg actatcttac aa #ttgaagaa   1020 ttggtgaagc aacttgtaga gacagtttca tgtggaggaa atcttttgat ga #atattggg   1080 cccacactag atggcaccat ttctgtagtt tttgaggagc gactgaggca ag #tggggtcc   1140 tggctaaaag tcaatggaga agctatttat gaaacctata cctggcgatc cc #agaatgac   1200 actgtcaccc cagatgtgtg gtacacatcc aagcctaaag aaaaattagt ct #atgccatt   1260 tttcttaaat ggcccacatc aggacagctg ttccttggcc atcccaaagc ta #ttctgggg   1320 gcaacagagg tgaaactact gggccatgga cagccactta actggatttc tt #tggagcaa   1380 aatggcatta tggtagaact gccacagcta accattcatc agatgccgtg ta #aatggggc   1440 tgggctctag ccctaactaa tgtgatctaa agtgcagcag agtggctgat gc #tgcaagtt   1500 atgtctaagg ctaggaacta tcaggtgtct ataattgtag cacatggaga aa #gcaatgta   1560 aactggataa gaaaattatt tggcagttca gccctttccc tttttcccac ta #aatttttc   1620 ttaaattacc catgtaacca ttttaactct ccagtgcact ttgccattaa ag #tctcttca   1680 cattgatttg tttccatgtg tgactcagag gtgagaattt tttcacatta ta #gtagcaag   1740 gaattggtgg tattatggac cgaactgaaa attttatgtt gaagccatat cc #cccatgat   1800 tatatagtta tgcatcactt aatatgggga tattttctgg gaaatgcatt gc #tagtcaat   1860 ttttttttgt gccaacatca tagagtgtat ttacaaaatc ctagatggca ta #gcctacta   1920 cacacctaat gtgtatggta tagactgttg ctcctaggct acagacatat ac #agcatgtt   1980 actgaatact gtaggcaata gtaacagtgg tatttgtata tcgaaacata tg #gaaacata   2040 gagaaggtac agtaaaaata ctgtaaaata aatggtgcac ctgtataggg ca #cttaccac   2100 gaatggagct tacaggactg gaagttgctc tgggtgagtc agtgagtgaa tg #tgaaggcc   2160 taggacatta ttgaacactg ccagacgtta taaatactgt atgcttaggc ta #cactacat   2220 ttataaaaaa aagtttttct ttcttcaatt ataaattaac ataagtgtac tg #taacttta   2280 caaacgtttt aatttttaaa acctttttgg ctcttttgta ataacactta gc #ttaaaaca   2340 taaactcatt gtgcaaatgt aa            #                   #               2362 <210> SEQ ID NO 195 <211> LENGTH: 467 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 195 Met Arg Pro Gln Glu Leu Pro Arg Leu Ala Ph #e Pro Leu Leu Leu Leu   1               5  #                 10  #                 15 Leu Leu Leu Leu Leu Pro Pro Pro Pro Cys Pr #o Ala His Ser Ala Thr              20      #             25      #             30 Arg Phe Asp Pro Thr Trp Glu Ser Leu Asp Al #a Arg Gln Leu Pro Ala          35          #         40          #         45 Trp Phe Asp Gln Ala Lys Phe Gly Ile Phe Il #e His Trp Gly Val Phe      50              #     55              #     60 Ser Val Pro Ser Phe Gly Ser Glu Trp Phe Tr #p Trp Tyr Trp Gln Lys  65                  # 70                  # 75                  # 80 Glu Lys Ile Pro Lys Tyr Val Glu Phe Met Ly #s Asp Asn Tyr Pro Pro                  85  #                 90  #                 95 Ser Phe Lys Tyr Glu Asp Phe Gly Pro Leu Ph #e Thr Ala Lys Phe Phe             100       #           105       #           110 Asn Ala Asn Gln Trp Ala Asp Ile Phe Gln Al #a Ser Gly Ala Lys Tyr         115           #       120           #       125 Ile Val Leu Thr Ser Lys His His Glu Gly Ph #e Thr Leu Trp Gly Ser     130               #   135               #   140 Glu Tyr Ser Trp Asn Trp Asn Ala Ile Asp Gl #u Gly Pro Lys Arg Asp 145                 1 #50                 1 #55                 1 #60 Ile Val Lys Glu Leu Glu Val Ala Ile Arg As #n Arg Thr Asp Leu Arg                 165   #               170   #               175 Phe Gly Leu Tyr Tyr Ser Leu Phe Glu Trp Ph #e His Pro Leu Phe Leu             180       #           185       #           190 Glu Asp Glu Ser Ser Ser Phe His Lys Arg Gl #n Phe Pro Val Ser Lys         195           #       200           #       205 Thr Leu Pro Glu Leu Tyr Glu Leu Val Asn As #n Tyr Gln Pro Glu Val     210               #   215               #   220 Leu Trp Ser Asp Gly Asp Gly Gly Ala Pro As #p Gln Tyr Trp Asn Ser 225                 2 #30                 2 #35                 2 #40 Thr Gly Phe Leu Ala Trp Leu Tyr Asn Glu Se #r Pro Val Arg Gly Thr                 245   #               250   #               255 Val Val Thr Asn Asp Arg Trp Gly Ala Gly Se #r Ile Cys Lys His Gly             260       #           265       #           270 Gly Phe Tyr Thr Cys Ser Asp Arg Tyr Asn Pr #o Gly His Leu Leu Pro         275           #       280           #       285 His Lys Trp Glu Asn Cys Met Thr Ile Asp Ly #s Leu Ser Trp Gly Tyr     290               #   295               #   300 Arg Arg Glu Ala Gly Ile Ser Asp Tyr Leu Th #r Ile Glu Glu Leu Val 305                 3 #10                 3 #15                 3 #20 Lys Gln Leu Val Glu Thr Val Ser Cys Gly Gl #y Asn Leu Leu Met Asn                 325   #               330   #               335 Ile Gly Pro Thr Leu Asp Gly Thr Ile Ser Va #l Val Phe Glu Glu Arg             340       #           345       #           350 Leu Arg Gln Val Gly Ser Trp Leu Lys Val As #n Gly Glu Ala Ile Tyr         355           #       360           #       365 Glu Thr Tyr Thr Trp Arg Ser Gln Asn Asp Th #r Val Thr Pro Asp Val     370               #   375               #   380 Trp Tyr Thr Ser Lys Pro Lys Glu Lys Leu Va #l Tyr Ala Ile Phe Leu 385                 3 #90                 3 #95                 4 #00 Lys Trp Pro Thr Ser Gly Gln Leu Phe Leu Gl #y His Pro Lys Ala Ile                 405   #               410   #               415 Leu Gly Ala Thr Glu Val Lys Leu Leu Gly Hi #s Gly Gln Pro Leu Asn             420       #           425       #           430 Trp Ile Ser Leu Glu Gln Asn Gly Ile Met Va #l Glu Leu Pro Gln Leu         435           #       440           #       445 Thr Ile His Gln Met Pro Cys Lys Trp Gly Tr #p Ala Leu Ala Leu Thr     450               #   455               #   460 Asn Val Ile 465 <210> SEQ ID NO 196 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 196 tggtttgacc aggccaagtt cgg            #                   #                23 <210> SEQ ID NO 197 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 197 ggattcatcc tcaaggaaga gcgg           #                   #                24 <210> SEQ ID NO 198 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 198 aacttgcagc atcagccact ctgc           #                   #                24 <210> SEQ ID NO 199 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 199 ttccgtgccc agcttcggta gcgagtggtt ctggtggtat tggca    #                   #45 <210> SEQ ID NO 200 <211> LENGTH: 2372 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 200 agcagggaaa tccggatgtc tcggttatga agtggagcag tgagtgtgag cc #tcaacata     60 gttccagaac tctccatccg gactagttat tgagcatctg cctctcatat ca #ccagtggc    120 catctgaggt gtttccctgg ctctgaaggg gtaggcacga tggccaggtg ct #tcagcctg    180 gtgttgcttc tcacttccat ctggaccacg aggctcctgg tccaaggctc tt #tgcgtgca    240 gaagagcttt ccatccaggt gtcatgcaga attatgggga tcacccttgt ga #gcaaaaag    300 gcgaaccagc agctgaattt cacagaagct aaggaggcct gtaggctgct gg #gactaagt    360 ttggccggca aggaccaagt tgaaacagcc ttgaaagcta gctttgaaac tt #gcagctat    420 ggctgggttg gagatggatt cgtggtcatc tctaggatta gcccaaaccc ca #agtgtggg    480 aaaaatgggg tgggtgtcct gatttggaag gttccagtga gccgacagtt tg #cagcctat    540 tgttacaact catctgatac ttggactaac tcgtgcattc cagaaattat ca #ccaccaaa    600 gatcccatat tcaacactca aactgcaaca caaacaacag aatttattgt ca #gtgacagt    660 acctactcgg tggcatcccc ttactctaca atacctgccc ctactactac tc #ctcctgct    720 ccagcttcca cttctattcc acggagaaaa aaattgattt gtgtcacaga ag #tttttatg    780 gaaactagca ccatgtctac agaaactgaa ccatttgttg aaaataaagc ag #cattcaag    840 aatgaagctg ctgggtttgg aggtgtcccc acggctctgc tagtgcttgc tc #tcctcttc    900 tttggtgctg cagctggtct tggattttgc tatgtcaaaa ggtatgtgaa gg #ccttccct    960 tttacaaaca agaatcagca gaaggaaatg atcgaaacca aagtagtaaa gg #aggagaag   1020 gccaatgata gcaaccctaa tgaggaatca aagaaaactg ataaaaaccc ag #aagagtcc   1080 aagagtccaa gcaaaactac cgtgcgatgc ctggaagctg aagtttagat ga #gacagaaa   1140 tgaggagaca cacctgaggc tggtttcttt catgctcctt accctgcccc ag #ctggggaa   1200 atcaaaaggg ccaaagaacc aaagaagaaa gtccaccctt ggttcctaac tg #gaatcagc   1260 tcaggactgc cattggacta tggagtgcac caaagagaat gcccttctcc tt #attgtaac   1320 cctgtctgga tcctatcctc ctacctccaa agcttcccac ggcctttcta gc #ctggctat   1380 gtcctaataa tatcccactg ggagaaagga gttttgcaaa gtgcaaggac ct #aaaacatc   1440 tcatcagtat ccagtggtaa aaaggcctcc tggctgtctg aggctaggtg gg #ttgaaagc   1500 caaggagtca ctgagaccaa ggctttctct actgattccg cagctcagac cc #tttcttca   1560 gctctgaaag agaaacacgt atcccacctg acatgtcctt ctgagcccgg ta #agagcaaa   1620 agaatggcag aaaagtttag cccctgaaag ccatggagat tctcataact tg #agacctaa   1680 tctctgtaaa gctaaaataa agaaatagaa caaggctgag gatacgacag ta #cactgtca   1740 gcagggactg taaacacaga cagggtcaaa gtgttttctc tgaacacatt ga #gttggaat   1800 cactgtttag aacacacaca cttacttttt ctggtctcta ccactgctga ta #ttttctct   1860 aggaaatata cttttacaag taacaaaaat aaaaactctt ataaatttct at #ttttatct   1920 gagttacaga aatgattact aaggaagatt actcagtaat ttgtttaaaa ag #taataaaa   1980 ttcaacaaac atttgctgaa tagctactat atgtcaagtg ctgtgcaagg ta #ttacactc   2040 tgtaattgaa tattattcct caaaaaattg cacatagtag aacgctatct gg #gaagctat   2100 ttttttcagt tttgatattt ctagcttatc tacttccaaa ctaattttta tt #tttgctga   2160 gactaatctt attcattttc tctaatatgg caaccattat aaccttaatt ta #ttattaac   2220 atacctaaga agtacattgt tacctctata taccaaagca cattttaaaa gt #gccattaa   2280 caaatgtatc actagccctc ctttttccaa caagaaggga ctgagagatg ca #gaaatatt   2340 tgtgacaaaa aattaaagca tttagaaaac tt        #                   #        2372 <210> SEQ ID NO 201 <211> LENGTH: 322 <212> TYPE: PRT <213> ORGANISM: Artificial sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic protein <400> SEQUENCE: 201 Met Ala Arg Cys Phe Ser Leu Val Leu Leu Le #u Thr Ser Ile Trp Thr   1               5  #                 10  #                 15 Thr Arg Leu Leu Val Gln Gly Ser Leu Arg Al #a Glu Glu Leu Ser Ile              20      #             25      #             30 Gln Val Ser Cys Arg Ile Met Gly Ile Thr Le #u Val Ser Lys Lys Ala          35          #         40          #         45 Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Gl #u Ala Cys Arg Leu Leu      50              #     55              #     60 Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Gl #u Thr Ala Leu Lys Ala  65                  # 70                  # 75                  # 80 Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val Gl #y Asp Gly Phe Val Val                  85  #                 90  #                 95 Ile Ser Arg Ile Ser Pro Asn Pro Lys Cys Gl #y Lys Asn Gly Val Gly             100       #           105       #           110 Val Leu Ile Trp Lys Val Pro Val Ser Arg Gl #n Phe Ala Ala Tyr Cys         115           #       120           #       125 Tyr Asn Ser Ser Asp Thr Trp Thr Asn Ser Cy #s Ile Pro Glu Ile Ile     130               #   135               #   140 Thr Thr Lys Asp Pro Ile Phe Asn Thr Gln Th #r Ala Thr Gln Thr Thr 145                 1 #50                 1 #55                 1 #60 Glu Phe Ile Val Ser Asp Ser Thr Tyr Ser Va #l Ala Ser Pro Tyr Ser                 165   #               170   #               175 Thr Ile Pro Ala Pro Thr Thr Thr Pro Pro Al #a Pro Ala Ser Thr Ser             180       #           185       #           190 Ile Pro Arg Arg Lys Lys Leu Ile Cys Val Th #r Glu Val Phe Met Glu         195           #       200           #       205 Thr Ser Thr Met Ser Thr Glu Thr Glu Pro Ph #e Val Glu Asn Lys Ala     210               #   215               #   220 Ala Phe Lys Asn Glu Ala Ala Gly Phe Gly Gl #y Val Pro Thr Ala Leu 225                 2 #30                 2 #35                 2 #40 Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Al #a Ala Gly Leu Gly Phe                 245   #               250   #               255 Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pr #o Phe Thr Asn Lys Asn             260       #           265       #           270 Gln Gln Lys Glu Met Ile Glu Thr Lys Val Va #l Lys Glu Glu Lys Ala         275           #       280           #       285 Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Ly #s Thr Asp Lys Asn Pro     290               #   295               #   300 Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Va #l Arg Cys Leu Glu Ala 305                 3 #10                 3 #15                 3 #20 Glu Val <210> SEQ ID NO 202 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 202 gagctttcca tccaggtgtc atgc           #                   #                24 <210> SEQ ID NO 203 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 203 gtcagtgaca gtacctactc gg            #                   #                 22 <210> SEQ ID NO 204 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 204 tggagcagga ggagtagtag tagg           #                   #                24 <210> SEQ ID NO 205 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 205 aggaggcctg taggctgctg ggactaagtt tggccggcaa ggaccaagtt   #              50 <210> SEQ ID NO 206 <211> LENGTH: 1620 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: modified_base <222> LOCATION: (973) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (977) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (996) <223> OTHER INFORMATION: a, t, c or g <221> NAME/KEY: modified_base <222> LOCATION: (1003) <223> OTHER INFORMATION: a, t, c or g <400> SEQUENCE: 206 agatggcggt cttggcacct ctaattgctc tcgtgtattc ggtgccgcga ct #ttcacgat     60 ggctcgccca accttactac cttctgtcgg ccctgctctc tgctgccttc ct #actcgtga    120 ggaaactgcc gccgctctgc cacggtctgc ccacccaacg cgaagacggt aa #cccgtgtg    180 actttgactg gagagaagtg gagatcctga tgtttctcag tgccattgtg at #gatgaaga    240 accgcagatc catcactgtg gagcaacata taggcaacat tttcatgttt ag #taaagtgg    300 ccaacacaat tcttttcttc cgcttggata ttcgcatggg cctactttac at #cacactct    360 gcatagtgtt cctgatgacg tgcaaacccc ccctatatat gggccctgag ta #tatcaagt    420 acttcaatga taaaaccatt gatgaggaac tagaacggga caagagggtc ac #ttggattg    480 tggagttctt tgccaattgg tctaatgact gccaatcatt tgcccctatc ta #tgctgacc    540 tctcccttaa atacaactgt acagggctaa attttgggaa ggtggatgtt gg #acgctata    600 ctgatgttag tacgcggtac aaagtgagca catcacccct caccaagcaa ct #ccctaccc    660 tgatcctgtt ccaaggtggc aaggaggcaa tgcggcggcc acagattgac aa #gaaaggac    720 gggctgtctc atggaccttc tctgaggaga atgtgatccg agaatttaac tt #aaatgagc    780 tataccagcg ggccaagaaa ctatcaaagg ctggagacaa tatccctgag ga #gcagcctg    840 tggcttcaac ccccaccaca gtgtcagatg gggaaaacaa gaaggataaa ta #agatcctc    900 actttggcag tgcttcctct cctgtcaatt ccaggctctt tccataacca ca #agcctgag    960 gctgcagcct ttnattnatg ttttcccttt ggctgngact ggntggggca gc #atgcagct   1020 tctgatttta aagaggcatc tagggaattg tcaggcaccc tacaggaagg cc #tgccatgc   1080 tgtggccaac tgtttcactg gagcaagaaa gagatctcat aggacggagg gg #gaaatggt   1140 ttccctccaa gcttgggtca gtgtgttaac tgcttatcag ctattcagac at #ctccatgg   1200 tttctccatg aaactctgtg gtttcatcat tccttcttag ttgacctgca ca #gcttggtt   1260 agacctagat ttaaccctaa ggtaagatgc tggggtatag aacgctaaga at #tttccccc   1320 aaggactctt gcttccttaa gcccttctgg cttcgtttat ggtcttcatt aa #aagtataa   1380 gcctaacttt gtcgctagtc ctaaggagaa acctttaacc acaaagtttt ta #tcattgaa   1440 gacaatattg aacaaccccc tattttgtgg ggattgagaa ggggtgaata ga #ggcttgag   1500 actttccttt gtgtggtagg acttggagga gaaatcccct ggactttcac ta #accctctg   1560 acatactccc cacacccagt tgatggcttt ccgtaataaa aagattggga tt #tccttttg   1620 <210> SEQ ID NO 207 <211> LENGTH: 296 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 207 Met Ala Val Leu Ala Pro Leu Ile Ala Leu Va #l Tyr Ser Val Pro Arg   1               5  #                 10  #                 15 Leu Ser Arg Trp Leu Ala Gln Pro Tyr Tyr Le #u Leu Ser Ala Leu Leu              20      #             25      #             30 Ser Ala Ala Phe Leu Leu Val Arg Lys Leu Pr #o Pro Leu Cys His Gly          35          #         40          #         45 Leu Pro Thr Gln Arg Glu Asp Gly Asn Pro Cy #s Asp Phe Asp Trp Arg      50              #     55              #     60 Glu Val Glu Ile Leu Met Phe Leu Ser Ala Il #e Val Met Met Lys Asn  65                  # 70                  # 75                  # 80 Arg Arg Ser Ile Thr Val Glu Gln His Ile Gl #y Asn Ile Phe Met Phe                  85  #                 90  #                 95 Ser Lys Val Ala Asn Thr Ile Leu Phe Phe Ar #g Leu Asp Ile Arg Met             100       #           105       #           110 Gly Leu Leu Tyr Ile Thr Leu Cys Ile Val Ph #e Leu Met Thr Cys Lys         115           #       120           #       125 Pro Pro Leu Tyr Met Gly Pro Glu Tyr Ile Ly #s Tyr Phe Asn Asp Lys     130               #   135               #   140 Thr Ile Asp Glu Glu Leu Glu Arg Asp Lys Ar #g Val Thr Trp Ile Val 145                 1 #50                 1 #55                 1 #60 Glu Phe Phe Ala Asn Trp Ser Asn Asp Cys Gl #n Ser Phe Ala Pro Ile                 165   #               170   #               175 Tyr Ala Asp Leu Ser Leu Lys Tyr Asn Cys Th #r Gly Leu Asn Phe Gly             180       #           185       #           190 Lys Val Asp Val Gly Arg Tyr Thr Asp Val Se #r Thr Arg Tyr Lys Val         195           #       200           #       205 Ser Thr Ser Pro Leu Thr Lys Gln Leu Pro Th #r Leu Ile Leu Phe Gln     210               #   215               #   220 Gly Gly Lys Glu Ala Met Arg Arg Pro Gln Il #e Asp Lys Lys Gly Arg 225                 2 #30                 2 #35                 2 #40 Ala Val Ser Trp Thr Phe Ser Glu Glu Asn Va #l Ile Arg Glu Phe Asn                 245   #               250   #               255 Leu Asn Glu Leu Tyr Gln Arg Ala Lys Lys Le #u Ser Lys Ala Gly Asp             260       #           265       #           270 Asn Ile Pro Glu Glu Gln Pro Val Ala Ser Th #r Pro Thr Thr Val Ser         275           #       280           #       285 Asp Gly Glu Asn Lys Lys Asp Lys     290               #   295 <210> SEQ ID NO 208 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 208 gcttggatat tcgcatgggc ctac           #                   #                24 <210> SEQ ID NO 209 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 209 tggagacaat atccctgagg             #                   #                   # 20 <210> SEQ ID NO 210 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 210 aacagttggc cacagcatgg cagg           #                   #                24 <210> SEQ ID NO 211 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 211 ccattgatga ggaactagaa cgggacaaga gggtcacttg gattgtggag   #              50 <210> SEQ ID NO 212 <211> LENGTH: 1985 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 212 ggacagctcg cggcccccga gagctctagc cgtcgaggag ctgcctgggg ac #gtttgccc     60 tggggcccca gcctggcccg ggtcaccctg gcatgaggag atgggcctgt tg #ctcctggt    120 cccattgctc ctgctgcccg gctcctacgg actgcccttc tacaacggct tc #tactactc    180 caacagcgcc aacgaccaga acctaggcaa cggtcatggc aaagacctcc tt #aatggagt    240 gaagctggtg gtggagacac ccgaggagac cctgttcacc taccaagggg cc #agtgtgat    300 cctgccctgc cgctaccgct acgagccggc cctggtctcc ccgcggcgtg tg #cgtgtcaa    360 atggtggaag ctgtcggaga acggggcccc agagaaggac gtgctggtgg cc #atcgggct    420 gaggcaccgc tcctttgggg actaccaagg ccgcgtgcac ctgcggcagg ac #aaagagca    480 tgacgtctcg ctggagatcc aggatctgcg gctggaggac tatgggcgtt ac #cgctgtga    540 ggtcattgac gggctggagg atgaaagcgg tctggtggag ctggagctgc gg #ggtgtggt    600 ctttccttac cagtccccca acgggcgcta ccagttcaac ttccacgagg gc #cagcaggt    660 ctgtgcagag caggctgcgg tggtggcctc ctttgagcag ctcttccggg cc #tgggagga    720 gggcctggac tggtgcaacg cgggctggct gcaggatgct acggtgcagt ac #cccatcat    780 gttgccccgg cagccctgcg gtggcccagg cctggcacct ggcgtgcgaa gc #tacggccc    840 ccgccaccgc cgcctgcacc gctatgatgt attctgcttc gctactgccc tc #aaggggcg    900 ggtgtactac ctggagcacc ctgagaagct gacgctgaca gaggcaaggg ag #gcctgcca    960 ggaagatgat gccacgatcg ccaaggtggg acagctcttt gccgcctgga ag #ttccatgg   1020 cctggaccgc tgcgacgctg gctggctggc agatggcagc gtccgctacc ct #gtggttca   1080 cccgcatcct aactgtgggc ccccagagcc tggggtccga agctttggct tc #cccgaccc   1140 gcagagccgc ttgtacggtg tttactgcta ccgccagcac taggacctgg gg #ccctcccc   1200 tgccgcattc cctcactggc tgtgtattta ttgagtggtt cgttttccct tg #tgggttgg   1260 agccatttta actgttttta tacttctcaa tttaaatttt ctttaaacat tt #ttttacta   1320 ttttttgtaa agcaaacaga acccaatgcc tccctttgct cctggatgcc cc #actccagg   1380 aatcatgctt gctcccctgg gccatttgcg gttttgtggg cttctggagg gt #tccccgcc   1440 atccaggctg gtctccctcc cttaaggagg ttggtgccca gagtgggcgg tg #gcctgtct   1500 agaatgccgc cgggagtccg ggcatggtgg gcacagttct ccctgcccct ca #gcctgggg   1560 gaagaagagg gcctcggggg cctccggagc tgggctttgg gcctctcctg cc #cacctcta   1620 cttctctgtg aagccgctga ccccagtctg cccactgagg ggctagggct gg #aagccagt   1680 tctaggcttc caggcgaaat ctgagggaag gaagaaactc ccctccccgt tc #cccttccc   1740 ctctcggttc caaagaatct gttttgttgt catttgtttc tcctgtttcc ct #gtgtgggg   1800 aggggccctc aggtgtgtgt actttggaca ataaatggtg ctatgactgc ct #tccgccaa   1860 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa #aaaaaaaa   1920 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa #aaaaaaaa   1980 aaaaa                  #                   #                   #          1985 <210> SEQ ID NO 213 <211> LENGTH: 360 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 213 Met Gly Leu Leu Leu Leu Val Pro Leu Leu Le #u Leu Pro Gly Ser Tyr   1               5  #                 10  #                 15 Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Se #r Asn Ser Ala Asn Asp              20      #             25      #             30 Gln Asn Leu Gly Asn Gly His Gly Lys Asp Le #u Leu Asn Gly Val Lys          35          #         40          #         45 Leu Val Val Glu Thr Pro Glu Glu Thr Leu Ph #e Thr Tyr Gln Gly Ala      50              #     55              #     60 Ser Val Ile Leu Pro Cys Arg Tyr Arg Tyr Gl #u Pro Ala Leu Val Ser  65                  # 70                  # 75                  # 80 Pro Arg Arg Val Arg Val Lys Trp Trp Lys Le #u Ser Glu Asn Gly Ala                  85  #                 90  #                 95 Pro Glu Lys Asp Val Leu Val Ala Ile Gly Le #u Arg His Arg Ser Phe             100       #           105       #           110 Gly Asp Tyr Gln Gly Arg Val His Leu Arg Gl #n Asp Lys Glu His Asp         115           #       120           #       125 Val Ser Leu Glu Ile Gln Asp Leu Arg Leu Gl #u Asp Tyr Gly Arg Tyr     130               #   135               #   140 Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Gl #u Ser Gly Leu Val Glu 145                 1 #50                 1 #55                 1 #60 Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gl #n Ser Pro Asn Gly Arg                 165   #               170   #               175 Tyr Gln Phe Asn Phe His Glu Gly Gln Gln Va #l Cys Ala Glu Gln Ala             180       #           185       #           190 Ala Val Val Ala Ser Phe Glu Gln Leu Phe Ar #g Ala Trp Glu Glu Gly         195           #       200           #       205 Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln As #p Ala Thr Val Gln Tyr     210               #   215               #   220 Pro Ile Met Leu Pro Arg Gln Pro Cys Gly Gl #y Pro Gly Leu Ala Pro 225                 2 #30                 2 #35                 2 #40 Gly Val Arg Ser Tyr Gly Pro Arg His Arg Ar #g Leu His Arg Tyr Asp                 245   #               250   #               255 Val Phe Cys Phe Ala Thr Ala Leu Lys Gly Ar #g Val Tyr Tyr Leu Glu             260       #           265       #           270 His Pro Glu Lys Leu Thr Leu Thr Glu Ala Ar #g Glu Ala Cys Gln Glu         275           #       280           #       285 Asp Asp Ala Thr Ile Ala Lys Val Gly Gln Le #u Phe Ala Ala Trp Lys     290               #   295               #   300 Phe His Gly Leu Asp Arg Cys Asp Ala Gly Tr #p Leu Ala Asp Gly Ser 305                 3 #10                 3 #15                 3 #20 Val Arg Tyr Pro Val Val His Pro His Pro As #n Cys Gly Pro Pro Glu                 325   #               330   #               335 Pro Gly Val Arg Ser Phe Gly Phe Pro Asp Pr #o Gln Ser Arg Leu Tyr             340       #           345       #           350 Gly Val Tyr Cys Tyr Arg Gln His         355           #       360 <210> SEQ ID NO 214 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 214 tgcttcgcta ctgccctc              #                   #                   #  18 <210> SEQ ID NO 215 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 215 ttcccttgtg ggttggag              #                   #                   #  18 <210> SEQ ID NO 216 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 216 agggctggaa gccagttc              #                   #                   #  18 <210> SEQ ID NO 217 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 217 agccagtgag gaaatgcg              #                   #                   #  18 <210> SEQ ID NO 218 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 218 tgtccaaagt acacacacct gagg           #                   #                24 <210> SEQ ID NO 219 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 219 gatgccacga tcgccaaggt gggacagctc tttgccgcct ggaag    #                   #45 <210> SEQ ID NO 220 <211> LENGTH: 1503 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 220 ggagagcgga gcgaagctgg ataacagggg accgatgatg tggcgaccat ca #gttctgct     60 gcttctgttg ctactgaggc acggggccca ggggaagcca tccccagacg ca #ggccctca    120 tggccagggg agggtgcacc aggcggcccc cctgagcgac gctccccatg at #gacgccca    180 cgggaacttc cagtacgacc atgaggcttt cctgggacgg gaagtggcca ag #gaattcga    240 ccaactcacc ccagaggaaa gccaggcccg tctggggcgg atcgtggacc gc #atggaccg    300 cgcgggggac ggcgacggct gggtgtcgct ggccgagctt cgcgcgtgga tc #gcgcacac    360 gcagcagcgg cacatacggg actcggtgag cgcggcctgg gacacgtacg ac #acggaccg    420 cgacgggcgt gtgggttggg aggagctgcg caacgccacc tatggccact ac #gcgcccgg    480 tgaagaattt catgacgtgg aggatgcaga gacctacaaa aagatgctgg ct #cgggacga    540 gcggcgtttc cgggtggccg accaggatgg ggactcgatg gccactcgag ag #gagctgac    600 agccttcctg caccccgagg agttccctca catgcgggac atcgtgattg ct #gaaaccct    660 ggaggacctg gacagaaaca aagatggcta tgtccaggtg gaggagtaca tc #gcggatct    720 gtactcagcc gagcctgggg aggaggagcc ggcgtgggtg cagacggaga gg #cagcagtt    780 ccgggacttc cgggatctga acaaggatgg gcacctggat gggagtgagg tg #ggccactg    840 ggtgctgccc cctgcccagg accagcccct ggtggaagcc aaccacctgc tg #cacgagag    900 cgacacggac aaggatgggc ggctgagcaa agcggaaatc ctgggtaatt gg #aacatgtt    960 tgtgggcagt caggccacca actatggcga ggacctgacc cggcaccacg at #gagctgtg   1020 agcaccgcgc acctgccaca gcctcagagg cccgcacaat gaccggagga gg #ggccgctg   1080 tggtctggcc ccctccctgt ccaggccccg caggaggcag atgcagtccc ag #gcatcctc   1140 ctgcccctgg gctctcaggg accccctggg tcggcttctg tccctgtcac ac #ccccaacc   1200 ccagggaggg gctgtcatag tcccagagga taagcaatac ctatttctga ct #gagtctcc   1260 cagcccagac ccagggaccc ttggccccaa gctcagctct aagaaccgcc cc #aacccctc   1320 cagctccaaa tctgagcctc caccacatag actgaaactc ccctggcccc ag #ccctctcc   1380 tgcctggcct ggcctgggac acctcctctc tgccaggagg caataaaagc ca #gcgccggg   1440 accttgaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa #aaaaaaaa   1500 aaa                   #                   #                   #           1503 <210> SEQ ID NO 221 <211> LENGTH: 328 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 221 Met Met Trp Arg Pro Ser Val Leu Leu Leu Le #u Leu Leu Leu Arg His   1               5  #                 10  #                 15 Gly Ala Gln Gly Lys Pro Ser Pro Asp Ala Gl #y Pro His Gly Gln Gly              20      #             25      #             30 Arg Val His Gln Ala Ala Pro Leu Ser Asp Al #a Pro His Asp Asp Ala          35          #         40          #         45 His Gly Asn Phe Gln Tyr Asp His Glu Ala Ph #e Leu Gly Arg Glu Val      50              #     55              #     60 Ala Lys Glu Phe Asp Gln Leu Thr Pro Glu Gl #u Ser Gln Ala Arg Leu  65                  # 70                  # 75                  # 80 Gly Arg Ile Val Asp Arg Met Asp Arg Ala Gl #y Asp Gly Asp Gly Trp                  85  #                 90  #                 95 Val Ser Leu Ala Glu Leu Arg Ala Trp Ile Al #a His Thr Gln Gln Arg             100       #           105       #           110 His Ile Arg Asp Ser Val Ser Ala Ala Trp As #p Thr Tyr Asp Thr Asp         115           #       120           #       125 Arg Asp Gly Arg Val Gly Trp Glu Glu Leu Ar #g Asn Ala Thr Tyr Gly     130               #   135               #   140 His Tyr Ala Pro Gly Glu Glu Phe His Asp Va #l Glu Asp Ala Glu Thr 145                 1 #50                 1 #55                 1 #60 Tyr Lys Lys Met Leu Ala Arg Asp Glu Arg Ar #g Phe Arg Val Ala Asp                 165   #               170   #               175 Gln Asp Gly Asp Ser Met Ala Thr Arg Glu Gl #u Leu Thr Ala Phe Leu             180       #           185       #           190 His Pro Glu Glu Phe Pro His Met Arg Asp Il #e Val Ile Ala Glu Thr         195           #       200           #       205 Leu Glu Asp Leu Asp Arg Asn Lys Asp Gly Ty #r Val Gln Val Glu Glu     210               #   215               #   220 Tyr Ile Ala Asp Leu Tyr Ser Ala Glu Pro Gl #y Glu Glu Glu Pro Ala 225                 2 #30                 2 #35                 2 #40 Trp Val Gln Thr Glu Arg Gln Gln Phe Arg As #p Phe Arg Asp Leu Asn                 245   #               250   #               255 Lys Asp Gly His Leu Asp Gly Ser Glu Val Gl #y His Trp Val Leu Pro             260       #           265       #           270 Pro Ala Gln Asp Gln Pro Leu Val Glu Ala As #n His Leu Leu His Glu         275           #       280           #       285 Ser Asp Thr Asp Lys Asp Gly Arg Leu Ser Ly #s Ala Glu Ile Leu Gly     290               #   295               #   300 Asn Trp Asn Met Phe Val Gly Ser Gln Ala Th #r Asn Tyr Gly Glu Asp 305                 3 #10                 3 #15                 3 #20 Leu Thr Arg His His Asp Glu Leu                 325 <210> SEQ ID NO 222 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 222 cgcaggccct catggccagg             #                   #                   # 20 <210> SEQ ID NO 223 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 223 gaaatcctgg gtaattgg              #                   #                   #  18 <210> SEQ ID NO 224 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 224 gtgcgcggtg ctcacagctc atc            #                   #                23 <210> SEQ ID NO 225 <211> LENGTH: 44 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 225 cccccctgag cgacgctccc ccatgatgac gcccacggga actt    #                   # 44 <210> SEQ ID NO 226 <211> LENGTH: 2403 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 226 ggggccttgc cttccgcact cgggcgcagc cgggtggatc tcgagcaggt gc #ggagcccc     60 gggcggcggg cgcgggtgcg agggatccct gacgcctctg tccctgtttc tt #tgtcgctc    120 ccagcctgtc tgtcgtcgtt ttggcgcccc cgcctccccg cggtgcgggg tt #gcacaccg    180 atcctgggct tcgctcgatt tgccgccgag gcgcctccca gacctagagg gg #cgctggcc    240 tggagcagcg ggtcgtctgt gtcctctctc ctctgcgccg cgcccgggga tc #cgaagggt    300 gcggggctct gaggaggtga cgcgcggggc ctcccgcacc ctggccttgc cc #gcattctc    360 cctctctccc aggtgtgagc agcctatcag tcaccatgtc cgcagcctgg at #cccggctc    420 tcggcctcgg tgtgtgtctg ctgctgctgc cggggcccgc gggcagcgag gg #agccgctc    480 ccattgctat cacatgtttt accagaggct tggacatcag gaaagagaaa gc #agatgtcc    540 tctgcccagg gggctgccct cttgaggaat tctctgtgta tgggaacata gt #atatgctt    600 ctgtatcgag catatgtggg gctgctgtcc acaggggagt aatcagcaac tc #agggggac    660 ctgtacgagt ctatagccta cctggtcgag aaaactattc ctcagtagat gc #caatggca    720 tccagtctca aatgctttct agatggtctg cttctttcac agtaactaaa gg #caaaagta    780 gtacacagga ggccacagga caagcagtgt ccacagcaca tccaccaaca gg #taaacgac    840 taaagaaaac acccgagaag aaaactggca ataaagattg taaagcagac at #tgcatttc    900 tgattgatgg aagctttaat attgggcagc gccgatttaa tttacagaag aa #ttttgttg    960 gaaaagtggc tctaatgttg ggaattggaa cagaaggacc acatgtgggc ct #tgttcaag   1020 ccagtgaaca tcccaaaata gaattttact tgaaaaactt tacatcagcc aa #agatgttt   1080 tgtttgccat aaaggaagta ggtttcagag ggggtaattc caatacagga aa #agccttga   1140 agcatactgc tcagaaattc ttcacggtag atgctggagt aagaaaaggg at #ccccaaag   1200 tggtggtggt atttattgat ggttggcctt ctgatgacat cgaggaagca gg #cattgtgg   1260 ccagagagtt tggtgtcaat gtatttatag tttctgtggc caagcctatc cc #tgaagaac   1320 tggggatggt tcaggatgtc acatttgttg acaaggctgt ctgtcggaat aa #tggcttct   1380 tctcttacca catgcccaac tggtttggca ccacaaaata cgtaaagcct ct #ggtacaga   1440 agctgtgcac tcatgaacaa atgatgtgca gcaagacctg ttataactca gt #gaacattg   1500 cctttctaat tgatggctcc agcagtgttg gagatagcaa tttccgcctc at #gcttgaat   1560 ttgtttccaa catagccaag acttttgaaa tctcggacat tggtgccaag at #agctgctg   1620 tacagtttac ttatgatcag cgcacggagt tcagtttcac tgactatagc ac #caaagaga   1680 atgtcctagc tgtcatcaga aacatccgct atatgagtgg tggaacagct ac #tggtgatg   1740 ccatttcctt cactgttaga aatgtgtttg gccctataag ggagagcccc aa #caagaact   1800 tcctagtaat tgtcacagat gggcagtcct atgatgatgt ccaaggccct gc #agctgctg   1860 cacatgatgc aggaatcact atcttctctg ttggtgtggc ttgggcacct ct #ggatgacc   1920 tgaaagatat ggcttctaaa ccgaaggagt ctcacgcttt cttcacaaga ga #gttcacag   1980 gattagaacc aattgtttct gatgtcatca gaggcatttg tagagatttc tt #agaatccc   2040 agcaataatg gtaacatttt gacaactgaa agaaaaagta caaggggatc ca #gtgtgtaa   2100 attgtattct cataatactg aaatgcttta gcatactaga atcagataca aa #actattaa   2160 gtatgtcaac agccatttag gcaaataagc actcctttaa agccgctgcc tt #ctggttac   2220 aatttacagt gtactttgtt aaaaacactg ctgaggcttc ataatcatgg ct #cttagaaa   2280 ctcaggaaag aggagataat gtggattaaa accttaagag ttctaaccat gc #ctactaaa   2340 tgtacagata tgcaaattcc atagctcaat aaaagaatct gatacttaga cc #aaaaaaaa   2400 aaa                   #                   #                   #           2403 <210> SEQ ID NO 227 <211> LENGTH: 550 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 227 Met Ser Ala Ala Trp Ile Pro Ala Leu Gly Le #u Gly Val Cys Leu Leu   1               5  #                 10  #                 15 Leu Leu Pro Gly Pro Ala Gly Ser Glu Gly Al #a Ala Pro Ile Ala Ile              20      #             25      #             30 Thr Cys Phe Thr Arg Gly Leu Asp Ile Arg Ly #s Glu Lys Ala Asp Val          35          #         40          #         45 Leu Cys Pro Gly Gly Cys Pro Leu Glu Glu Ph #e Ser Val Tyr Gly Asn      50              #     55              #     60 Ile Val Tyr Ala Ser Val Ser Ser Ile Cys Gl #y Ala Ala Val His Arg  65                  # 70                  # 75                  # 80 Gly Val Ile Ser Asn Ser Gly Gly Pro Val Ar #g Val Tyr Ser Leu Pro                  85  #                 90  #                 95 Gly Arg Glu Asn Tyr Ser Ser Val Asp Ala As #n Gly Ile Gln Ser Gln             100       #           105       #           110 Met Leu Ser Arg Trp Ser Ala Ser Phe Thr Va #l Thr Lys Gly Lys Ser         115           #       120           #       125 Ser Thr Gln Glu Ala Thr Gly Gln Ala Val Se #r Thr Ala His Pro Pro     130               #   135               #   140 Thr Gly Lys Arg Leu Lys Lys Thr Pro Glu Ly #s Lys Thr Gly Asn Lys 145                 1 #50                 1 #55                 1 #60 Asp Cys Lys Ala Asp Ile Ala Phe Leu Ile As #p Gly Ser Phe Asn Ile                 165   #               170   #               175 Gly Gln Arg Arg Phe Asn Leu Gln Lys Asn Ph #e Val Gly Lys Val Ala             180       #           185       #           190 Leu Met Leu Gly Ile Gly Thr Glu Gly Pro Hi #s Val Gly Leu Val Gln         195           #       200           #       205 Ala Ser Glu His Pro Lys Ile Glu Phe Tyr Le #u Lys Asn Phe Thr Ser     210               #   215               #   220 Ala Lys Asp Val Leu Phe Ala Ile Lys Glu Va #l Gly Phe Arg Gly Gly 225                 2 #30                 2 #35                 2 #40 Asn Ser Asn Thr Gly Lys Ala Leu Lys His Th #r Ala Gln Lys Phe Phe                 245   #               250   #               255 Thr Val Asp Ala Gly Val Arg Lys Gly Ile Pr #o Lys Val Val Val Val             260       #           265       #           270 Phe Ile Asp Gly Trp Pro Ser Asp Asp Ile Gl #u Glu Ala Gly Ile Val         275           #       280           #       285 Ala Arg Glu Phe Gly Val Asn Val Phe Ile Va #l Ser Val Ala Lys Pro     290               #   295               #   300 Ile Pro Glu Glu Leu Gly Met Val Gln Asp Va #l Thr Phe Val Asp Lys 305                 3 #10                 3 #15                 3 #20 Ala Val Cys Arg Asn Asn Gly Phe Phe Ser Ty #r His Met Pro Asn Trp                 325   #               330   #               335 Phe Gly Thr Thr Lys Tyr Val Lys Pro Leu Va #l Gln Lys Leu Cys Thr             340       #           345       #           350 His Glu Gln Met Met Cys Ser Lys Thr Cys Ty #r Asn Ser Val Asn Ile         355           #       360           #       365 Ala Phe Leu Ile Asp Gly Ser Ser Ser Val Gl #y Asp Ser Asn Phe Arg     370               #   375               #   380 Leu Met Leu Glu Phe Val Ser Asn Ile Ala Ly #s Thr Phe Glu Ile Ser 385                 3 #90                 3 #95                 4 #00 Asp Ile Gly Ala Lys Ile Ala Ala Val Gln Ph #e Thr Tyr Asp Gln Arg                 405   #               410   #               415 Thr Glu Phe Ser Phe Thr Asp Tyr Ser Thr Ly #s Glu Asn Val Leu Ala             420       #           425       #           430 Val Ile Arg Asn Ile Arg Tyr Met Ser Gly Gl #y Thr Ala Thr Gly Asp         435           #       440           #       445 Ala Ile Ser Phe Thr Val Arg Asn Val Phe Gl #y Pro Ile Arg Glu Ser     450               #   455               #   460 Pro Asn Lys Asn Phe Leu Val Ile Val Thr As #p Gly Gln Ser Tyr Asp 465                 4 #70                 4 #75                 4 #80 Asp Val Gln Gly Pro Ala Ala Ala Ala His As #p Ala Gly Ile Thr Ile                 485   #               490   #               495 Phe Ser Val Gly Val Ala Trp Ala Pro Leu As #p Asp Leu Lys Asp Met             500       #           505       #           510 Ala Ser Lys Pro Lys Glu Ser His Ala Phe Ph #e Thr Arg Glu Phe Thr         515           #       520           #       525 Gly Leu Glu Pro Ile Val Ser Asp Val Ile Ar #g Gly Ile Cys Arg Asp     530               #   535               #   540 Phe Leu Glu Ser Gln Gln 545                 5 #50 <210> SEQ ID NO 228 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 228 tggtctcgca caccgatc              #                   #                   #  18 <210> SEQ ID NO 229 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 229 ctgctgtcca caggggag              #                   #                   #  18 <210> SEQ ID NO 230 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 230 ccttgaagca tactgctc              #                   #                   #  18 <210> SEQ ID NO 231 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 231 gagatagcaa tttccgcc              #                   #                   #  18 <210> SEQ ID NO 232 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 232 ttcctcaaga gggcagcc              #                   #                   #  18 <210> SEQ ID NO 233 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 233 cttggcacca atgtccgaga tttc           #                   #                24 <210> SEQ ID NO 234 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial  #Sequence: Synthetic       oligonucleotide probe <400> SEQUENCE: 234 gctctgagga aggtgacgcg cggggcctcc gaacccttgg ccttg    #                   #45 <210> SEQ ID NO 235 <211> LENGTH: 2586 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 235 cgccgcgctc ccgcacccgc ggcccgccca ccgcgccgct cccgcatctg ca #cccgcagc     60 ccggcggcct cccggcggga gcgagcagat ccagtccggc ccgcagcgca ac #tcggtcca    120 gtcggggcgg cggctgcggg cgcagagcgg agatgcagcg gcttggggcc ac #cctgctgt    180 gcctgctgct ggcggcggcg gtccccacgg cccccgcgcc cgctccgacg gc #gacctcgg    240 ctccagtcaa gcccggcccg gctctcagct acccgcagga ggaggccacc ct #caatgaga    300 tgttccgcga ggttgaggaa ctgatggagg acacgcagca caaattgcgc ag #cgcggtgg    360 aagagatgga ggcagaagaa gctgctgcta aagcatcatc agaagtgaac ct #ggcaaact    420 tacctcccag ctatcacaat gagaccaaca cagacacgaa ggttggaaat aa #taccatcc    480 atgtgcaccg agaaattcac aagataacca acaaccagac tggacaaatg gt #cttttcag    540 agacagttat cacatctgtg ggagacgaag aaggcagaag gagccacgag tg #catcatcg    600 acgaggactg tgggcccagc atgtactgcc agtttgccag cttccagtac ac #ctgccagc    660 catgccgggg ccagaggatg ctctgcaccc gggacagtga gtgctgtgga ga #ccagctgt    720 gtgtctgggg tcactgcacc aaaatggcca ccaggggcag caatgggacc at #ctgtgaca    780 accagaggga ctgccagccg gggctgtgct gtgccttcca gagaggcctg ct #gttccctg    840 tgtgcacacc cctgcccgtg gagggcgagc tttgccatga ccccgccagc cg #gcttctgg    900 acctcatcac ctgggagcta gagcctgatg gagccttgga ccgatgccct tg #tgccagtg    960 gcctcctctg ccagccccac agccacagcc tggtgtatgt gtgcaagccg ac #cttcgtgg   1020 ggagccgtga ccaagatggg gagatcctgc tgcccagaga ggtccccgat ga #gtatgaag   1080 ttggcagctt catggaggag gtgcgccagg agctggagga cctggagagg ag #cctgactg   1140 aagagatggc gctgggggag cctgcggctg ccgccgctgc actgctggga gg #ggaagaga   1200 tttagatctg gaccaggctg tgggtagatg tgcaatagaa atagctaatt ta #tttcccca   1260 ggtgtgtgct ttaggcgtgg gctgaccagg cttcttccta catcttcttc cc #agtaagtt   1320 tcccctctgg cttgacagca tgaggtgttg tgcatttgtt cagctccccc ag #gctgttct   1380 ccaggcttca cagtctggtg cttgggagag tcaggcaggg ttaaactgca gg #agcagttt   1440 gccacccctg tccagattat tggctgcttt gcctctacca gttggcagac ag #ccgtttgt   1500 tctacatggc tttgataatt gtttgagggg aggagatgga aacaatgtgg ag #tctccctc   1560 tgattggttt tggggaaatg tggagaagag tgccctgctt tgcaaacatc aa #cctggcaa   1620 aaatgcaaca aatgaatttt ccacgcagtt ctttccatgg gcataggtaa gc #tgtgcctt   1680 cagctgttgc agatgaaatg ttctgttcac cctgcattac atgtgtttat tc #atccagca   1740 gtgttgctca gctcctacct ctgtgccagg gcagcatttt catatccaag at #caattccc   1800 tctctcagca cagcctgggg agggggtcat tgttctcctc gtccatcagg ga #tctcagag   1860 gctcagagac tgcaagctgc ttgcccaagt cacacagcta gtgaagacca ga #gcagtttc   1920 atctggttgt gactctaagc tcagtgctct ctccactacc ccacaccagc ct #tggtgcca   1980 ccaaaagtgc tccccaaaag gaaggagaat gggatttttc ttgaggcatg ca #catctgga   2040 attaaggtca aactaattct cacatccctc taaaagtaaa ctactgttag ga #acagcagt   2100 gttctcacag tgtggggcag ccgtccttct aatgaagaca atgatattga ca #ctgtccct   2160 ctttggcagt tgcattagta actttgaaag gtatatgact gagcgtagca ta #caggttaa   2220 cctgcagaaa cagtacttag gtaattgtag ggcgaggatt ataaatgaaa tt #tgcaaaat   2280 cacttagcag caactgaaga caattatcaa ccacgtggag aaaatcaaac cg #agcagggc   2340 tgtgtgaaac atggttgtaa tatgcgactg cgaacactga actctacgcc ac #tccacaaa   2400 tgatgttttc aggtgtcatg gactgttgcc accatgtatt catccagagt tc #ttaaagtt   2460 taaagttgca catgattgta taagcatgct ttctttgagt tttaaattat gt #ataaacat   2520 aagttgcatt tagaaatcaa gcataaatca cttcaactgc aaaaaaaaaa aa #aaaaaaaa   2580 aaaaaa                  #                   #                   #         2586 <210> SEQ ID NO 236 <211> LENGTH: 350 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 236 Met Gln Arg Leu Gly Ala Thr Leu Leu Cys Le #u Leu Leu Ala Ala Ala   1               5  #                 10  #                 15 Val Pro Thr Ala Pro Ala Pro Ala Pro Thr Al #a Thr Ser Ala Pro Val              20      #             25      #             30 Lys Pro Gly Pro Ala Leu Ser Tyr Pro Gln Gl #u Glu Ala Thr Leu Asn          35          #         40          #         45 Glu Met Phe Arg Glu Val Glu Glu Leu Met Gl #u Asp Thr Gln His Lys      50              #     55              #     60 Leu Arg Ser Ala Val Glu Glu Met Glu Ala Gl #u Glu Ala Ala Ala Lys  65                  # 70                  # 75                  # 80 Ala Ser Ser Glu Val Asn Leu Ala Asn Leu Pr #o Pro Ser Tyr His Asn                  85  #                 90  #                 95 Glu Thr Asn Thr Asp Thr Lys Val Gly Asn As #n Thr Ile His Val His             100       #           105       #           110 Arg Glu Ile His Lys Ile Thr Asn Asn Gln Th #r Gly Gln Met Val Phe         115           #       120           #       125 Ser Glu Thr Val Ile Thr Ser Val Gly Asp Gl #u Glu Gly Arg Arg Ser     130               #   135               #   140 His Glu Cys Ile Ile Asp Glu Asp Cys Gly Pr #o Ser Met Tyr Cys Gln 145                 1 #50                 1 #55                 1 #60 Phe Ala Ser Phe Gln Tyr Thr Cys Gln Pro Cy #s Arg Gly Gln Arg Met                 165   #               170   #               175 Leu Cys Thr Arg Asp Ser Glu Cys Cys Gly As #p Gln Leu Cys Val Trp             180       #           185       #           190 Gly His Cys Thr Lys Met Ala Thr Arg Gly Se #r Asn Gly Thr Ile Cys         195           #       200           #       205 Asp Asn Gln Arg Asp Cys Gln Pro Gly Leu Cy #s Cys Ala Phe Gln Arg     210               #   215               #   220 Gly Leu Leu Phe Pro Val Cys Thr Pro Leu Pr #o Val Glu Gly Glu Leu 225                 2 #30                 2 #35                 2 #40 Cys His Asp Pro Ala Ser Arg Leu Leu Asp Le #u Ile Thr Trp Glu Leu                 245   #               250   #               255 Glu Pro Asp Gly Ala Leu Asp Arg Cys Pro Cy #s Ala Ser Gly Leu Leu             260       #           265       #           270 Cys Gln Pro His Ser His Ser Leu Val Tyr Va #l Cys Lys Pro Thr Phe         275           #       280           #       285 Val Gly Ser Arg Asp Gln Asp Gly Glu Ile Le #u Leu Pro Arg Glu Val     290               #   295               #   300 Pro Asp Glu Tyr Glu Val Gly Ser Phe Met Gl #u Glu Val Arg Gln Glu 305                 3 #10                 3 #15                 3 #20 Leu Glu Asp Leu Glu Arg Ser Leu Thr Glu Gl #u Met Ala Leu Gly Glu                 325   #               330   #               335 Pro Ala Ala Ala Ala Ala Ala Leu Leu Gly Gl #y Glu Glu Ile             340       #           345       #           350 <210> SEQ ID NO 237 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 237 ggagctgcac cccttgc              #                   #                   #   17 <210> SEQ ID NO 238 <211> LENGTH: 49 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 238 ggaggactgt gccaccatga gagactcttc aaacccaagg caaaattgg   #              49 <210> SEQ ID NO 239 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 239 gcagagcgga gatgcagcgg cttg           #                   #               24 <210> SEQ ID NO 240 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 240 ttggcagctt catggagg              #                   #                   # 18 <210> SEQ ID NO 241 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 241 cctgggcaaa aatgcaac              #                   #                   # 18 <210> SEQ ID NO 242 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 242 ctccagctcc tggcgcacct cctc           #                   #                24 <210> SEQ ID NO 243 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 243 ggctctcagc taccgcgcag gagcgaggcc accctcaatg agatg    #                   #45 <210> SEQ ID NO 244 <211> LENGTH: 3679 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 244 aaggaggctg ggaggaaaga ggtaagaaag gttagagaac ctacctcaca   #              50 tctctctggg ctcagaagga ctctgaagat aacaataatt tcagcccatc   #             100 cactctcctt ccctcccaaa cacacatgtg catgtacaca cacacataca   #             150 cacacataca ccttcctctc cttcactgaa gactcacagt cactcactct   #             200 gtgagcaggt catagaaaag gacactaaag ccttaaggac aggcctggcc   #             250 attacctctg cagctccttt ggcttgttga gtcaaaaaac atgggagggg   #             300 ccaggcacgg tgactcacac ctgtaatccc agcattttgg gagaccgagg   #             350 tgagcagatc acttgaggtc aggagttcga gaccagcctg gccaacatgg   #             400 agaaaccccc atctctacta aaaatacaaa aattagccag gagtggtggc   #             450 aggtgcctgt aatcccagct actcaggtgg ctgagccagg agaatcgctt   #             500 gaatccagga ggcggaggat gcagtcagct gagtgcaccg ctgcactcca   #             550 gcctgggtga cagaatgaga ctctgtctca aacaaacaaa cacgggagga   #             600 ggggtagata ctgcttctct gcaacctcct taactctgca tcctcttctt   #             650 ccagggctgc ccctgatggg gcctggcaat gactgagcag gcccagcccc   #             700 agaggacaag gaagagaagg catattgagg agggcaagaa gtgacgcccg   #             750 gtgtagaatg actgccctgg gagggtggtt ccttgggccc tggcagggtt   #             800 gctgaccctt accctgcaaa acacaaagag caggactcca gactctcctt   #             850 gtgaatggtc ccctgccctg cagctccacc atgaggcttc tcgtggcccc   #             900 actcttgcta gcttgggtgg ctggtgccac tgccactgtg cccgtggtac   #             950 cctggcatgt tccctgcccc cctcagtgtg cctgccagat ccggccctgg   #            1000 tatacgcccc gctcgtccta ccgcgaggct accactgtgg actgcaatga   #            1050 cctattcctg acggcagtcc ccccggcact ccccgcaggc acacagaccc   #            1100 tgctcctgca gagcaacagc attgtccgtg tggaccagag tgagctgggc   #            1150 tacctggcca atctcacaga gctggacctg tcccagaaca gcttttcgga   #            1200 tgcccgagac tgtgatttcc atgccctgcc ccagctgctg agcctgcacc   #            1250 tagaggagaa ccagctgacc cggctggagg accacagctt tgcagggctg   #            1300 gccagcctac aggaactcta tctcaaccac aaccagctct accgcatcgc   #            1350 ccccagggcc ttttctggcc tcagcaactt gctgcggctg cacctcaact   #            1400 ccaacctcct gagggccatt gacagccgct ggtttgaaat gctgcccaac   #            1450 ttggagatac tcatgattgg cggcaacaag gtagatgcca tcctggacat   #            1500 gaacttccgg cccctggcca acctgcgtag cctggtgcta gcaggcatga   #            1550 acctgcggga gatctccgac tatgccctgg aggggctgca aagcctggag   #            1600 agcctctcct tctatgacaa ccagctggcc cgggtgccca ggcgggcact   #            1650 ggaacaggtg cccgggctca agttcctaga cctcaacaag aacccgctcc   #            1700 agcgggtagg gccgggggac tttgccaaca tgctgcacct taaggagctg   #            1750 ggactgaaca acatggagga gctggtctcc atcgacaagt ttgccctggt   #            1800 gaacctcccc gagctgacca agctggacat caccaataac ccacggctgt   #            1850 ccttcatcca cccccgcgcc ttccaccacc tgccccagat ggagaccctc   #            1900 atgctcaaca acaacgctct cagtgccttg caccagcaga cggtggagtc   #            1950 cctgcccaac ctgcaggagg taggtctcca cggcaacccc atccgctgtg   #            2000 actgtgtcat ccgctgggcc aatgccacgg gcacccgtgt ccgcttcatc   #            2050 gagccgcaat ccaccctgtg tgcggagcct ccggacctcc agcgcctccc   #            2100 ggtccgtgag gtgcccttcc gggagatgac ggaccactgt ttgcccctca   #            2150 tctccccacg aagcttcccc ccaagcctcc aggtagccag tggagagagc   #            2200 atggtgctgc attgccgggc actggccgaa cccgaacccg agatctactg   #            2250 ggtcactcca gctgggcttc gactgacacc tgcccatgca ggcaggaggt   #            2300 accgggtgta ccccgagggg accctggagc tgcggagggt gacagcagaa   #            2350 gaggcagggc tatacacctg tgtggcccag aacctggtgg gggctgacac   #            2400 taagacggtt agtgtggttg tgggccgtgc tctcctccag ccaggcaggg   #            2450 acgaaggaca ggggctggag ctccgggtgc aggagaccca cccctatcac   #            2500 atcctgctat cttgggtcac cccacccaac acagtgtcca ccaacctcac   #            2550 ctggtccagt gcctcctccc tccggggcca gggggccaca gctctggccc   #            2600 gcctgcctcg gggaacccac agctacaaca ttacccgcct ccttcaggcc   #            2650 acggagtact gggcctgcct gcaagtggcc tttgctgatg cccacaccca   #            2700 gttggcttgt gtatgggcca ggaccaaaga ggccacttct tgccacagag   #            2750 ccttagggga tcgtcctggg ctcattgcca tcctggctct cgctgtcctt   #            2800 ctcctggcag ctgggctagc ggcccacctt ggcacaggcc aacccaggaa   #            2850 gggtgtgggt gggaggcggc ctctccctcc agcctgggct ttctggggct   #            2900 ggagtgcccc ttctgtccgg gttgtgtctg ctcccctcgt cctgccctgg   #            2950 aatccaggga ggaagctgcc cagatcctca gaaggggaga cactgttgcc   #            3000 accattgtct caaaattctt gaagctcagc ctgttctcag cagtagagaa   #            3050 atcactagga ctacttttta ccaaaagaga agcagtctgg gccagatgcc   #            3100 ctgccaggaa agggacatgg acccacgtgc ttgaggcctg gcagctgggc   #            3150 caagacagat ggggctttgt ggccctgggg gtgcttctgc agccttgaaa   #            3200 aagttgccct tacctcctag ggtcacctct gctgccattc tgaggaacat   #            3250 ctccaaggaa caggagggac tttggctaga gcctcctgcc tccccatctt   #            3300 ctctctgccc agaggctcct gggcctggct tggctgtccc ctacctgtgt   #            3350 ccccgggctg caccccttcc tcttctcttt ctctgtacag tctcagttgc   #            3400 ttgctcttgt gcctcctggg caagggctga aggaggccac tccatctcac   #            3450 ctcggggggc tgccctcaat gtgggagtga ccccagccag atctgaagga   #            3500 catttgggag agggatgccc aggaacgcct catctcagca gcctgggctc   #            3550 ggcattccga agctgacttt ctataggcaa ttttgtacct ttgtggagaa   #            3600 atgtgtcacc tcccccaacc cgattcactc ttttctcctg ttttgtaaaa   #            3650 aataaaaata aataataaca ataaaaaaa          #                   #          3679 <210> SEQ ID NO 245 <211> LENGTH: 713 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 245 Met Arg Leu Leu Val Ala Pro Leu Leu Leu Al #a Trp Val Ala Gly   1               5  #                 10  #                 15 Ala Thr Ala Thr Val Pro Val Val Pro Trp Hi #s Val Pro Cys Pro                  20  #                 25  #                 30 Pro Gln Cys Ala Cys Gln Ile Arg Pro Trp Ty #r Thr Pro Arg Ser                  35  #                 40  #                 45 Ser Tyr Arg Glu Ala Thr Thr Val Asp Cys As #n Asp Leu Phe Leu                  50  #                 55  #                 60 Thr Ala Val Pro Pro Ala Leu Pro Ala Gly Th #r Gln Thr Leu Leu                  65  #                 70  #                 75 Leu Gln Ser Asn Ser Ile Val Arg Val Asp Gl #n Ser Glu Leu Gly                  80  #                 85  #                 90 Tyr Leu Ala Asn Leu Thr Glu Leu Asp Leu Se #r Gln Asn Ser Phe                  95  #                100  #                105 Ser Asp Ala Arg Asp Cys Asp Phe His Ala Le #u Pro Gln Leu Leu                 110   #               115   #               120 Ser Leu His Leu Glu Glu Asn Gln Leu Thr Ar #g Leu Glu Asp His                 125   #               130   #               135 Ser Phe Ala Gly Leu Ala Ser Leu Gln Glu Le #u Tyr Leu Asn His                 140   #               145   #               150 Asn Gln Leu Tyr Arg Ile Ala Pro Arg Ala Ph #e Ser Gly Leu Ser                 155   #               160   #               165 Asn Leu Leu Arg Leu His Leu Asn Ser Asn Le #u Leu Arg Ala Ile                 170   #               175   #               180 Asp Ser Arg Trp Phe Glu Met Leu Pro Asn Le #u Glu Ile Leu Met                 185   #               190   #               195 Ile Gly Gly Asn Lys Val Asp Ala Ile Leu As #p Met Asn Phe Arg                 200   #               205   #               210 Pro Leu Ala Asn Leu Arg Ser Leu Val Leu Al #a Gly Met Asn Leu                 215   #               220   #               225 Arg Glu Ile Ser Asp Tyr Ala Leu Glu Gly Le #u Gln Ser Leu Glu                 230   #               235   #               240 Ser Leu Ser Phe Tyr Asp Asn Gln Leu Ala Ar #g Val Pro Arg Arg                 245   #               250   #               255 Ala Leu Glu Gln Val Pro Gly Leu Lys Phe Le #u Asp Leu Asn Lys                 260   #               265   #               270 Asn Pro Leu Gln Arg Val Gly Pro Gly Asp Ph #e Ala Asn Met Leu                 275   #               280   #               285 His Leu Lys Glu Leu Gly Leu Asn Asn Met Gl #u Glu Leu Val Ser                 290   #               295   #               300 Ile Asp Lys Phe Ala Leu Val Asn Leu Pro Gl #u Leu Thr Lys Leu                 305   #               310   #               315 Asp Ile Thr Asn Asn Pro Arg Leu Ser Phe Il #e His Pro Arg Ala                 320   #               325   #               330 Phe His His Leu Pro Gln Met Glu Thr Leu Me #t Leu Asn Asn Asn                 335   #               340   #               345 Ala Leu Ser Ala Leu His Gln Gln Thr Val Gl #u Ser Leu Pro Asn                 350   #               355   #               360 Leu Gln Glu Val Gly Leu His Gly Asn Pro Il #e Arg Cys Asp Cys                 365   #               370   #               375 Val Ile Arg Trp Ala Asn Ala Thr Gly Thr Ar #g Val Arg Phe Ile                 380   #               385   #               390 Glu Pro Gln Ser Thr Leu Cys Ala Glu Pro Pr #o Asp Leu Gln Arg                 395   #               400   #               405 Leu Pro Val Arg Glu Val Pro Phe Arg Glu Me #t Thr Asp His Cys                 410   #               415   #               420 Leu Pro Leu Ile Ser Pro Arg Ser Phe Pro Pr #o Ser Leu Gln Val                 425   #               430   #               435 Ala Ser Gly Glu Ser Met Val Leu His Cys Ar #g Ala Leu Ala Glu                 440   #               445   #               450 Pro Glu Pro Glu Ile Tyr Trp Val Thr Pro Al #a Gly Leu Arg Leu                 455   #               460   #               465 Thr Pro Ala His Ala Gly Arg Arg Tyr Arg Va #l Tyr Pro Glu Gly                 470   #               475   #               480 Thr Leu Glu Leu Arg Arg Val Thr Ala Glu Gl #u Ala Gly Leu Tyr                 485   #               490   #               495 Thr Cys Val Ala Gln Asn Leu Val Gly Ala As #p Thr Lys Thr Val                 500   #               505   #               510 Ser Val Val Val Gly Arg Ala Leu Leu Gln Pr #o Gly Arg Asp Glu                 515   #               520   #               525 Gly Gln Gly Leu Glu Leu Arg Val Gln Glu Th #r His Pro Tyr His                 530   #               535   #               540 Ile Leu Leu Ser Trp Val Thr Pro Pro Asn Th #r Val Ser Thr Asn                 545   #               550   #               555 Leu Thr Trp Ser Ser Ala Ser Ser Leu Arg Gl #y Gln Gly Ala Thr                 560   #               565   #               570 Ala Leu Ala Arg Leu Pro Arg Gly Thr His Se #r Tyr Asn Ile Thr                 575   #               580   #               585 Arg Leu Leu Gln Ala Thr Glu Tyr Trp Ala Cy #s Leu Gln Val Ala                 590   #               595   #               600 Phe Ala Asp Ala His Thr Gln Leu Ala Cys Va #l Trp Ala Arg Thr                 605   #               610   #               615 Lys Glu Ala Thr Ser Cys His Arg Ala Leu Gl #y Asp Arg Pro Gly                 620   #               625   #               630 Leu Ile Ala Ile Leu Ala Leu Ala Val Leu Le #u Leu Ala Ala Gly                 635   #               640   #               645 Leu Ala Ala His Leu Gly Thr Gly Gln Pro Ar #g Lys Gly Val Gly                 650   #               655   #               660 Gly Arg Arg Pro Leu Pro Pro Ala Trp Ala Ph #e Trp Gly Trp Ser                 665   #               670   #               675 Ala Pro Ser Val Arg Val Val Ser Ala Pro Le #u Val Leu Pro Trp                 680   #               685   #               690 Asn Pro Gly Arg Lys Leu Pro Arg Ser Ser Gl #u Gly Glu Thr Leu                 695   #               700   #               705 Leu Pro Pro Leu Ser Gln Asn Ser                 710 <210> SEQ ID NO 246 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 246 aacaaggtaa gatgccatcc tg            #                   #                 22 <210> SEQ ID NO 247 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 247 aaacttgtcg atggagacca gctc           #                   #                24 <210> SEQ ID NO 248 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 248 aggggctgca aagcctggag agcctctcct tctatgacaa ccagc    #                   #45 <210> SEQ ID NO 249 <211> LENGTH: 3401 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 249 gcaagccaag gcgctgtttg agaaggtgaa gaagttccgg acccatgtgg   #              50 aggaggggga cattgtgtac cgcctctaca tgcggcagac catcatcaag   #             100 gtgatcaagt tcatcctcat catctgctac accgtctact acgtgcacaa   #             150 catcaagttc gacgtggact gcaccgtgga cattgagagc ctgacgggct   #             200 accgcaccta ccgctgtgcc caccccctgg ccacactctt caagatcctg   #             250 gcgtccttct acatcagcct agtcatcttc tacggcctca tctgcatgta   #             300 cacactgtgg tggatgctac ggcgctccct caagaagtac tcgtttgagt   #             350 cgatccgtga ggagagcagc tacagcgaca tccccgacgt caagaacgac   #             400 ttcgccttca tgctgcacct cattgaccaa tacgacccgc tctactccaa   #             450 gcgcttcgcc gtcttcctgt cggaggtgag tgagaacaag ctgcggcagc   #             500 tgaacctcaa caacgagtgg acgctggaca agctccggca gcggctcacc   #             550 aagaacgcgc aggacaagct ggagctgcac ctgttcatgc tcagtggcat   #             600 ccctgacact gtgtttgacc tggtggagct ggaggtcctc aagctggagc   #             650 tgatccccga cgtgaccatc ccgcccagca ttgcccagct cacgggcctc   #             700 aaggagctgt ggctctacca cacagcggcc aagattgaag cgcctgcgct   #             750 ggccttcctg cgcgagaacc tgcgggcgct gcacatcaag ttcaccgaca   #             800 tcaaggagat cccgctgtgg atctatagcc tgaagacact ggaggagctg   #             850 cacctgacgg gcaacctgag cgcggagaac aaccgctaca tcgtcatcga   #             900 cgggctgcgg gagctcaaac gcctcaaggt gctgcggctc aagagcaacc   #             950 taagcaagct gccacaggtg gtcacagatg tgggcgtgca cctgcagaag   #            1000 ctgtccatca acaatgaggg caccaagctc atcgtcctca acagcctcaa   #            1050 gaagatggcg aacctgactg agctggagct gatccgctgc gacctggagc   #            1100 gcatccccca ctccatcttc agcctccaca acctgcagga gattgacctc   #            1150 aaggacaaca acctcaagac catcgaggag atcatcagct tccagcacct   #            1200 gcaccgcctc acctgcctta agctgtggta caaccacatc gcctacatcc   #            1250 ccatccagat cggcaacctc accaacctgg agcgcctcta cctgaaccgc   #            1300 aacaagatcg agaagatccc cacccagctc ttctactgcc gcaagctgcg   #            1350 ctacctggac ctcagccaca acaacctgac cttcctccct gccgacatcg   #            1400 gcctcctgca gaacctccag aacctagcca tcacggccaa ccggatcgag   #            1450 acgctccctc cggagctctt ccagtgccgg aagctgcggg ccctgcacct   #            1500 gggcaacaac gtgctgcagt cactgccctc cagggtgggc gagctgacca   #            1550 acctgacgca gatcgagctg cggggcaacc ggctggagtg cctgcctgtg   #            1600 gagctgggcg agtgcccact gctcaagcgc agcggcttgg tggtggagga   #            1650 ggacctgttc aacacactgc cacccgaggt gaaggagcgg ctgtggaggg   #            1700 ctgacaagga gcaggcctga gcgaggccgg cccagcacag caagcagcag   #            1750 gaccgctgcc cagtcctcag gcccggaggg gcaggcctag cttctcccag   #            1800 aactcccgga cagccaggac agcctcgcgg ctgggcagga gcctggggcc   #            1850 gcttgtgagt caggccagag cgagaggaca gtatctgtgg ggctggcccc   #            1900 ttttctccct ctgagactca cgtcccccag ggcaagtgct tgtggaggag   #            1950 agcaagtctc aagagcgcag tatttggata atcagggtct cctccctgga   #            2000 ggccagctct gccccagggg ctgagctgcc accagaggtc ctgggaccct   #            2050 cactttagtt cttggtattt atttttctcc atctcccacc tccttcatcc   #            2100 agataactta tacattccca agaaagttca gcccagatgg aaggtgttca   #            2150 gggaaaggtg ggctgccttt tccccttgtc cttatttagc gatgccgccg   #            2200 ggcatttaac acccacctgg acttcagcag agtggtccgg ggcgaaccag   #            2250 ccatgggacg gtcacccagc agtgccgggc tgggctctgc ggtgcggtcc   #            2300 acgggagagc aggcctccag ctggaaaggc caggcctgga gcttgcctct   #            2350 tcagtttttg tggcagtttt agttttttgt tttttttttt tttaatcaaa   #            2400 aaacaatttt ttttaaaaaa aagctttgaa aatggatggt ttgggtatta   #            2450 aaaagaaaaa aaaaacttaa aaaaaaaaag acactaacgg ccagtgagtt   #            2500 ggagtctcag ggcagggtgg cagtttccct tgagcaaagc agccagacgt   #            2550 tgaactgtgt ttcctttccc tgggcgcagg gtgcagggtg tcttccggat   #            2600 ctggtgtgac cttggtccag gagttctatt tgttcctggg gagggaggtt   #            2650 tttttgtttg ttttttgggt ttttttggtg tcttgttttc tttctcctcc   #            2700 atgtgtcttg gcaggcactc atttctgtgg ctgtcggcca gagggaatgt   #            2750 tctggagctg ccaaggaggg aggagactcg ggttggctaa tccccggatg   #            2800 aacggtgctc cattcgcacc tcccctcctc gtgcctgccc tgcctctcca   #            2850 cgcacagtgt taaggagcca agaggagcca cttcgcccag actttgtttc   #            2900 cccacctcct gcggcatggg tgtgtccagt gccaccgctg gcctccgctg   #            2950 cttccatcag ccctgtcgcc acctggtcct tcatgaagag cagacactta   #            3000 gaggctggtc gggaatgggg aggtcgcccc tgggagggca ggcgttggtt   #            3050 ccaagccggt tcccgtccct ggcgcctgga gtgcacacag cccagtcggc   #            3100 acctggtggc tggaagccaa cctgctttag atcactcggg tccccacctt   #            3150 agaagggtcc ccgccttaga tcaatcacgt ggacactaag gcacgtttta   #            3200 gagtctcttg tcttaatgat tatgtccatc cgtctgtccg tccatttgtg   #            3250 ttttctgcgt cgtgtcattg gatataatcc tcagaaataa tgcacactag   #            3300 cctctgacaa ccatgaagca aaaatccgtt acatgtgggt ctgaacttgt   #            3350 agactcggtc acagtatcaa ataaaatcta taacagaaaa aaaaaaaaaa   #            3400 a                   #                   #                   #             3401 <210> SEQ ID NO 250 <211> LENGTH: 546 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 250 Met Arg Gln Thr Ile Ile Lys Val Ile Lys Ph #e Ile Leu Ile Ile   1               5  #                 10  #                 15 Cys Tyr Thr Val Tyr Tyr Val His Asn Ile Ly #s Phe Asp Val Asp                  20  #                 25  #                 30 Cys Thr Val Asp Ile Glu Ser Leu Thr Gly Ty #r Arg Thr Tyr Arg                  35  #                 40  #                 45 Cys Ala His Pro Leu Ala Thr Leu Phe Lys Il #e Leu Ala Ser Phe                  50  #                 55  #                 60 Tyr Ile Ser Leu Val Ile Phe Tyr Gly Leu Il #e Cys Met Tyr Thr                  65  #                 70  #                 75 Leu Trp Trp Met Leu Arg Arg Ser Leu Lys Ly #s Tyr Ser Phe Glu                  80  #                 85  #                 90 Ser Ile Arg Glu Glu Ser Ser Tyr Ser Asp Il #e Pro Asp Val Lys                  95  #                100  #                105 Asn Asp Phe Ala Phe Met Leu His Leu Ile As #p Gln Tyr Asp Pro                 110   #               115   #               120 Leu Tyr Ser Lys Arg Phe Ala Val Phe Leu Se #r Glu Val Ser Glu                 125   #               130   #               135 Asn Lys Leu Arg Gln Leu Asn Leu Asn Asn Gl #u Trp Thr Leu Asp                 140   #               145   #               150 Lys Leu Arg Gln Arg Leu Thr Lys Asn Ala Gl #n Asp Lys Leu Glu                 155   #               160   #               165 Leu His Leu Phe Met Leu Ser Gly Ile Pro As #p Thr Val Phe Asp                 170   #               175   #               180 Leu Val Glu Leu Glu Val Leu Lys Leu Glu Le #u Ile Pro Asp Val                 185   #               190   #               195 Thr Ile Pro Pro Ser Ile Ala Gln Leu Thr Gl #y Leu Lys Glu Leu                 200   #               205   #               210 Trp Leu Tyr His Thr Ala Ala Lys Ile Glu Al #a Pro Ala Leu Ala                 215   #               220   #               225 Phe Leu Arg Glu Asn Leu Arg Ala Leu His Il #e Lys Phe Thr Asp                 230   #               235   #               240 Ile Lys Glu Ile Pro Leu Trp Ile Tyr Ser Le #u Lys Thr Leu Glu                 245   #               250   #               255 Glu Leu His Leu Thr Gly Asn Leu Ser Ala Gl #u Asn Asn Arg Tyr                 260   #               265   #               270 Ile Val Ile Asp Gly Leu Arg Glu Leu Lys Ar #g Leu Lys Val Leu                 275   #               280   #               285 Arg Leu Lys Ser Asn Leu Ser Lys Leu Pro Gl #n Val Val Thr Asp                 290   #               295   #               300 Val Gly Val His Leu Gln Lys Leu Ser Ile As #n Asn Glu Gly Thr                 305   #               310   #               315 Lys Leu Ile Val Leu Asn Ser Leu Lys Lys Me #t Ala Asn Leu Thr                 320   #               325   #               330 Glu Leu Glu Leu Ile Arg Cys Asp Leu Glu Ar #g Ile Pro His Ser                 335   #               340   #               345 Ile Phe Ser Leu His Asn Leu Gln Glu Ile As #p Leu Lys Asp Asn                 350   #               355   #               360 Asn Leu Lys Thr Ile Glu Glu Ile Ile Ser Ph #e Gln His Leu His                 365   #               370   #               375 Arg Leu Thr Cys Leu Lys Leu Trp Tyr Asn Hi #s Ile Ala Tyr Ile                 380   #               385   #               390 Pro Ile Gln Ile Gly Asn Leu Thr Asn Leu Gl #u Arg Leu Tyr Leu                 395   #               400   #               405 Asn Arg Asn Lys Ile Glu Lys Ile Pro Thr Gl #n Leu Phe Tyr Cys                 410   #               415   #               420 Arg Lys Leu Arg Tyr Leu Asp Leu Ser His As #n Asn Leu Thr Phe                 425   #               430   #               435 Leu Pro Ala Asp Ile Gly Leu Leu Gln Asn Le #u Gln Asn Leu Ala                 440   #               445   #               450 Ile Thr Ala Asn Arg Ile Glu Thr Leu Pro Pr #o Glu Leu Phe Gln                 455   #               460   #               465 Cys Arg Lys Leu Arg Ala Leu His Leu Gly As #n Asn Val Leu Gln                 470   #               475   #               480 Ser Leu Pro Ser Arg Val Gly Glu Leu Thr As #n Leu Thr Gln Ile                 485   #               490   #               495 Glu Leu Arg Gly Asn Arg Leu Glu Cys Leu Pr #o Val Glu Leu Gly                 500   #               505   #               510 Glu Cys Pro Leu Leu Lys Arg Ser Gly Leu Va #l Val Glu Glu Asp                 515   #               520   #               525 Leu Phe Asn Thr Leu Pro Pro Glu Val Lys Gl #u Arg Leu Trp Arg                 530   #               535   #               540 Ala Asp Lys Glu Gln Ala                 545 <210> SEQ ID NO 251 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 251 caacaatgag ggcaccaagc             #                   #                   # 20 <210> SEQ ID NO 252 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 252 gatggctagg ttctggaggt tctg           #                   #                24 <210> SEQ ID NO 253 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 253 caacctgcag gagattgacc tcaaggacaa caacctcaag accatcg    #                47 <210> SEQ ID NO 254 <211> LENGTH: 1650 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 254 gcctgttgct gatgctgccg tgcggtactt gtcatggagc tggcactgcg   #              50 gcgctctccc gtcccgcggt ggttgctgct gctgccgctg ctgctgggcc   #             100 tgaacgcagg agctgtcatt gactggccca cagaggaggg caaggaagta   #             150 tgggattatg tgacggtccg caaggatgcc tacatgttct ggtggctcta   #             200 ttatgccacc aactcctgca agaacttctc agaactgccc ctggtcatgt   #             250 ggcttcaggg cggtccaggc ggttctagca ctggatttgg aaactttgag   #             300 gaaattgggc cccttgacag tgatctcaaa ccacggaaaa ccacctggct   #             350 ccaggctgcc agtctcctat ttgtggataa tcccgtgggc actgggttca   #             400 gttatgtgaa tggtagtggt gcctatgcca aggacctggc tatggtggct   #             450 tcagacatga tggttctcct gaagaccttc ttcagttgcc acaaagaatt   #             500 ccagacagtt ccattctaca ttttctcaga gtcctatgga ggaaaaatgg   #             550 cagctggcat tggtctagag ctttataagg ccattcagcg agggaccatc   #             600 aagtgcaact ttgcgggggt tgccttgggt gattcctgga tctcccctgt   #             650 tgattcggtg ctctcctggg gaccttacct gtacagcatg tctcttctcg   #             700 aagacaaagg tctggcagag gtgtctaagg ttgcagagca agtactgaat   #             750 gccgtaaata aggggctcta cagagaggcc acagagctgt gggggaaagc   #             800 agaaatgatc attgaacaga acacagatgg ggtgaacttc tataacatct   #             850 taactaaaag cactcccacg tctacaatgg agtcgagtct agaattcaca   #             900 cagagccacc tagtttgtct ttgtcagcgc cacgtgagac acctacaacg   #             950 agatgcctta agccagctca tgaatggccc catcagaaag aagctcaaaa   #            1000 ttattcctga ggatcaatcc tggggaggcc aggctaccaa cgtctttgtg   #            1050 aacatggagg aggacttcat gaagccagtc attagcattg tggacgagtt   #            1100 gctggaggca gggatcaacg tgacggtgta taatggacag ctggatctca   #            1150 tcgtagatac catgggtcag gaggcctggg tgcggaaact gaagtggcca   #            1200 gaactgccta aattcagtca gctgaagtgg aaggccctgt acagtgaccc   #            1250 taaatctttg gaaacatctg cttttgtcaa gtcctacaag aaccttgctt   #            1300 tctactggat tctgaaagct ggtcatatgg ttccttctga ccaaggggac   #            1350 atggctctga agatgatgag actggtgact cagcaagaat aggatggatg   #            1400 gggctggaga tgagctggtt tggccttggg gcacagagct gagctgaggc   #            1450 cgctgaagct gtaggaagcg ccattcttcc ctgtatctaa ctggggctgt   #            1500 gatcaagaag gttctgacca gcttctgcag aggataaaat cattgtctct   #            1550 ggaggcaatt tggaaattat ttctgcttct taaaaaaacc taagattttt   #            1600 taaaaaattg atttgttttg atcaaaataa aggatgataa tagatattaa   #            1650 <210> SEQ ID NO 255 <211> LENGTH: 452 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 255 Met Glu Leu Ala Leu Arg Arg Ser Pro Val Pr #o Arg Trp Leu Leu   1               5  #                 10  #                 15 Leu Leu Pro Leu Leu Leu Gly Leu Asn Ala Gl #y Ala Val Ile Asp                  20  #                 25  #                 30 Trp Pro Thr Glu Glu Gly Lys Glu Val Trp As #p Tyr Val Thr Val                  35  #                 40  #                 45 Arg Lys Asp Ala Tyr Met Phe Trp Trp Leu Ty #r Tyr Ala Thr Asn                  50  #                 55  #                 60 Ser Cys Lys Asn Phe Ser Glu Leu Pro Leu Va #l Met Trp Leu Gln                  65  #                 70  #                 75 Gly Gly Pro Gly Gly Ser Ser Thr Gly Phe Gl #y Asn Phe Glu Glu                  80  #                 85  #                 90 Ile Gly Pro Leu Asp Ser Asp Leu Lys Pro Ar #g Lys Thr Thr Trp                  95  #                100  #                105 Leu Gln Ala Ala Ser Leu Leu Phe Val Asp As #n Pro Val Gly Thr                 110   #               115   #               120 Gly Phe Ser Tyr Val Asn Gly Ser Gly Ala Ty #r Ala Lys Asp Leu                 125   #               130   #               135 Ala Met Val Ala Ser Asp Met Met Val Leu Le #u Lys Thr Phe Phe                 140   #               145   #               150 Ser Cys His Lys Glu Phe Gln Thr Val Pro Ph #e Tyr Ile Phe Ser                 155   #               160   #               165 Glu Ser Tyr Gly Gly Lys Met Ala Ala Gly Il #e Gly Leu Glu Leu                 170   #               175   #               180 Tyr Lys Ala Ile Gln Arg Gly Thr Ile Lys Cy #s Asn Phe Ala Gly                 185   #               190   #               195 Val Ala Leu Gly Asp Ser Trp Ile Ser Pro Va #l Asp Ser Val Leu                 200   #               205   #               210 Ser Trp Gly Pro Tyr Leu Tyr Ser Met Ser Le #u Leu Glu Asp Lys                 215   #               220   #               225 Gly Leu Ala Glu Val Ser Lys Val Ala Glu Gl #n Val Leu Asn Ala                 230   #               235   #               240 Val Asn Lys Gly Leu Tyr Arg Glu Ala Thr Gl #u Leu Trp Gly Lys                 245   #               250   #               255 Ala Glu Met Ile Ile Glu Gln Asn Thr Asp Gl #y Val Asn Phe Tyr                 260   #               265   #               270 Asn Ile Leu Thr Lys Ser Thr Pro Thr Ser Th #r Met Glu Ser Ser                 275   #               280   #               285 Leu Glu Phe Thr Gln Ser His Leu Val Cys Le #u Cys Gln Arg His                 290   #               295   #               300 Val Arg His Leu Gln Arg Asp Ala Leu Ser Gl #n Leu Met Asn Gly                 305   #               310   #               315 Pro Ile Arg Lys Lys Leu Lys Ile Ile Pro Gl #u Asp Gln Ser Trp                 320   #               325   #               330 Gly Gly Gln Ala Thr Asn Val Phe Val Asn Me #t Glu Glu Asp Phe                 335   #               340   #               345 Met Lys Pro Val Ile Ser Ile Val Asp Glu Le #u Leu Glu Ala Gly                 350   #               355   #               360 Ile Asn Val Thr Val Tyr Asn Gly Gln Leu As #p Leu Ile Val Asp                 365   #               370   #               375 Thr Met Gly Gln Glu Ala Trp Val Arg Lys Le #u Lys Trp Pro Glu                 380   #               385   #               390 Leu Pro Lys Phe Ser Gln Leu Lys Trp Lys Al #a Leu Tyr Ser Asp                 395   #               400   #               405 Pro Lys Ser Leu Glu Thr Ser Ala Phe Val Ly #s Ser Tyr Lys Asn                 410   #               415   #               420 Leu Ala Phe Tyr Trp Ile Leu Lys Ala Gly Hi #s Met Val Pro Ser                 425   #               430   #               435 Asp Gln Gly Asp Met Ala Leu Lys Met Met Ar #g Leu Val Thr Gln                 440   #               445   #               450 Gln Glu <210> SEQ ID NO 256 <211> LENGTH: 1100 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 256 ggccgcggga gaggaggcca tgggcgcgcg cggggcgctg ctgctggcgc   #              50 tgctgctggc tcgggctgga ctcaggaagc cggagtcgca ggaggcggcg   #             100 ccgttatcag gaccatgcgg ccgacgggtc atcacgtcgc gcatcgtggg   #             150 tggagaggac gccgaactcg ggcgttggcc gtggcagggg agcctgcgcc   #             200 tgtgggattc ccacgtatgc ggagtgagcc tgctcagcca ccgctgggca   #             250 ctcacggcgg cgcactgctt tgaaacctat agtgacctta gtgatccctc   #             300 cgggtggatg gtccagtttg gccagctgac ttccatgcca tccttctgga   #             350 gcctgcaggc ctactacacc cgttacttcg tatcgaatat ctatctgagc   #             400 cctcgctacc tggggaattc accctatgac attgccttgg tgaagctgtc   #             450 tgcacctgtc acctacacta aacacatcca gcccatctgt ctccaggcct   #             500 ccacatttga gtttgagaac cggacagact gctgggtgac tggctggggg   #             550 tacatcaaag aggatgaggc actgccatct ccccacaccc tccaggaagt   #             600 tcaggtcgcc atcataaaca actctatgtg caaccacctc ttcctcaagt   #             650 acagtttccg caaggacatc tttggagaca tggtttgtgc tggcaacgcc   #             700 caaggcggga aggatgcctg cttcggtgac tcaggtggac ccttggcctg   #             750 taacaagaat ggactgtggt atcagattgg agtcgtgagc tggggagtgg   #             800 gctgtggtcg gcccaatcgg cccggtgtct acaccaatat cagccaccac   #             850 tttgagtgga tccagaagct gatggcccag agtggcatgt cccagccaga   #             900 cccctcctgg ccactactct ttttccctct tctctgggct ctcccactcc   #             950 tggggccggt ctgagcctac ctgagcccat gcagcctggg gccactgcca   #            1000 agtcaggccc tggttctctt ctgtcttgtt tggtaataaa cacattccag   #            1050 ttgatgcctt gcagggcatt cttcaaaaaa aaaaaaaaaa aaaaaaaaaa   #            1100 <210> SEQ ID NO 257 <211> LENGTH: 314 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 257 Met Gly Ala Arg Gly Ala Leu Leu Leu Ala Le #u Leu Leu Ala Arg   1               5  #                 10  #                 15 Ala Gly Leu Arg Lys Pro Glu Ser Gln Glu Al #a Ala Pro Leu Ser                  20  #                 25  #                 30 Gly Pro Cys Gly Arg Arg Val Ile Thr Ser Ar #g Ile Val Gly Gly                  35  #                 40  #                 45 Glu Asp Ala Glu Leu Gly Arg Trp Pro Trp Gl #n Gly Ser Leu Arg                  50  #                 55  #                 60 Leu Trp Asp Ser His Val Cys Gly Val Ser Le #u Leu Ser His Arg                  65  #                 70  #                 75 Trp Ala Leu Thr Ala Ala His Cys Phe Glu Th #r Tyr Ser Asp Leu                  80  #                 85  #                 90 Ser Asp Pro Ser Gly Trp Met Val Gln Phe Gl #y Gln Leu Thr Ser                  95  #                100  #                105 Met Pro Ser Phe Trp Ser Leu Gln Ala Tyr Ty #r Thr Arg Tyr Phe                 110   #               115   #               120 Val Ser Asn Ile Tyr Leu Ser Pro Arg Tyr Le #u Gly Asn Ser Pro                 125   #               130   #               135 Tyr Asp Ile Ala Leu Val Lys Leu Ser Ala Pr #o Val Thr Tyr Thr                 140   #               145   #               150 Lys His Ile Gln Pro Ile Cys Leu Gln Ala Se #r Thr Phe Glu Phe                 155   #               160   #               165 Glu Asn Arg Thr Asp Cys Trp Val Thr Gly Tr #p Gly Tyr Ile Lys                 170   #               175   #               180 Glu Asp Glu Ala Leu Pro Ser Pro His Thr Le #u Gln Glu Val Gln                 185   #               190   #               195 Val Ala Ile Ile Asn Asn Ser Met Cys Asn Hi #s Leu Phe Leu Lys                 200   #               205   #               210 Tyr Ser Phe Arg Lys Asp Ile Phe Gly Asp Me #t Val Cys Ala Gly                 215   #               220   #               225 Asn Ala Gln Gly Gly Lys Asp Ala Cys Phe Gl #y Asp Ser Gly Gly                 230   #               235   #               240 Pro Leu Ala Cys Asn Lys Asn Gly Leu Trp Ty #r Gln Ile Gly Val                 245   #               250   #               255 Val Ser Trp Gly Val Gly Cys Gly Arg Pro As #n Arg Pro Gly Val                 260   #               265   #               270 Tyr Thr Asn Ile Ser His His Phe Glu Trp Il #e Gln Lys Leu Met                 275   #               280   #               285 Ala Gln Ser Gly Met Ser Gln Pro Asp Pro Se #r Trp Pro Leu Leu                 290   #               295   #               300 Phe Phe Pro Leu Leu Trp Ala Leu Pro Leu Le #u Gly Pro Val                 305   #               310 <210> SEQ ID NO 258 <211> LENGTH: 2427 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 258 cccacgcgtc cgcggacgcg tgggaagggc agaatgggac tccaagcctg   #              50 cctcctaggg ctctttgccc tcatcctctc tggcaaatgc agttacagcc   #             100 cggagcccga ccagcggagg acgctgcccc caggctgggt gtccctgggc   #             150 cgtgcggacc ctgaggaaga gctgagtctc acctttgccc tgagacagca   #             200 gaatgtggaa agactctcgg agctggtgca ggctgtgtcg gatcccagct   #             250 ctcctcaata cggaaaatac ctgaccctag agaatgtggc tgatctggtg   #             300 aggccatccc cactgaccct ccacacggtg caaaaatggc tcttggcagc   #             350 cggagcccag aagtgccatt ctgtgatcac acaggacttt ctgacttgct   #             400 ggctgagcat ccgacaagca gagctgctgc tccctggggc tgagtttcat   #             450 cactatgtgg gaggacctac ggaaacccat gttgtaaggt ccccacatcc   #             500 ctaccagctt ccacaggcct tggcccccca tgtggacttt gtggggggac   #             550 tgcaccgttt tcccccaaca tcatccctga ggcaacgtcc tgagccgcag   #             600 gtgacaggga ctgtaggcct gcatctgggg gtaaccccct ctgtgatccg   #             650 taagcgatac aacttgacct cacaagacgt gggctctggc accagcaata   #             700 acagccaagc ctgtgcccag ttcctggagc agtatttcca tgactcagac   #             750 ctggctcagt tcatgcgcct cttcggtggc aactttgcac atcaggcatc   #             800 agtagcccgt gtggttggac aacagggccg gggccgggcc gggattgagg   #             850 ccagtctaga tgtgcagtac ctgatgagtg ctggtgccaa catctccacc   #             900 tgggtctaca gtagccctgg ccggcatgag ggacaggagc ccttcctgca   #             950 gtggctcatg ctgctcagta atgagtcagc cctgccacat gtgcatactg   #            1000 tgagctatgg agatgatgag gactccctca gcagcgccta catccagcgg   #            1050 gtcaacactg agctcatgaa ggctgccgct cggggtctca ccctgctctt   #            1100 cgcctcaggt gacagtgggg ccgggtgttg gtctgtctct ggaagacacc   #            1150 agttccgccc taccttccct gcctccagcc cctatgtcac cacagtggga   #            1200 ggcacatcct tccaggaacc tttcctcatc acaaatgaaa ttgttgacta   #            1250 tatcagtggt ggtggcttca gcaatgtgtt cccacggcct tcataccagg   #            1300 aggaagctgt aacgaagttc ctgagctcta gcccccacct gccaccatcc   #            1350 agttacttca atgccagtgg ccgtgcctac ccagatgtgg ctgcactttc   #            1400 tgatggctac tgggtggtca gcaacagagt gcccattcca tgggtgtccg   #            1450 gaacctcggc ctctactcca gtgtttgggg ggatcctatc cttgatcaat   #            1500 gagcacagga tccttagtgg ccgcccccct cttggctttc tcaacccaag   #            1550 gctctaccag cagcatgggg caggtctctt tgatgtaacc cgtggctgcc   #            1600 atgagtcctg tctggatgaa gaggtagagg gccagggttt ctgctctggt   #            1650 cctggctggg atcctgtaac aggctgggga acaccaactt cccagctttg   #            1700 ctgaagactc tactcaaccc ctgacccttt cctatcagga gagatggctt   #            1750 gtcccctgcc ctgaagctgg cagttcagtc ccttattctg ccctgttgga   #            1800 agccctgctg aaccctcaac tattgactgc tgcagacagc ttatctccct   #            1850 aaccctgaaa tgctgtgagc ttgacttgac tcccaaccct accatgctcc   #            1900 atcatactca ggtctcccta ctcctgcctt agattcctca ataagatgct   #            1950 gtaactagca ttttttgaat gcctctccct ccgcatctca tctttctctt   #            2000 ttcaatcagg cttttccaaa gggttgtata cagactctgt gcactatttc   #            2050 acttgatatt cattccccaa ttcactgcaa ggagacctct actgtcaccg   #            2100 tttactcttt cctaccctga catccagaaa caatggcctc cagtgcatac   #            2150 ttctcaatct ttgctttatg gcctttccat catagttgcc cactccctct   #            2200 ccttacttag cttccaggtc ttaacttctc tgactactct tgtcttcctc   #            2250 tctcatcaat ttctgcttct tcatggaatg ctgaccttca ttgctccatt   #            2300 tgtagatttt tgctcttctc agtttactca ttgtcccctg gaacaaatca   #            2350 ctgacatcta caaccattac catctcacta aataagactt tctatccaat   #            2400 aatgattgat acctcaaatg taaaaaa           #                   #           2427 <210> SEQ ID NO 259 <211> LENGTH: 556 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 259 Met Gly Leu Gln Ala Cys Leu Leu Gly Leu Ph #e Ala Leu Ile Leu   1               5  #                 10  #                 15 Ser Gly Lys Cys Ser Tyr Ser Pro Glu Pro As #p Gln Arg Arg Thr                  20  #                 25  #                 30 Leu Pro Pro Gly Trp Val Ser Leu Gly Arg Al #a Asp Pro Glu Glu                  35  #                 40  #                 45 Glu Leu Ser Leu Thr Phe Ala Leu Arg Gln Gl #n Asn Val Glu Arg                  50  #                 55  #                 60 Leu Ser Glu Leu Val Gln Ala Val Ser Asp Pr #o Ser Ser Pro Gln                  65  #                 70  #                 75 Tyr Gly Lys Tyr Leu Thr Leu Glu Asn Val Al #a Asp Leu Val Arg                  80  #                 85  #                 90 Pro Ser Pro Leu Thr Leu His Thr Val Gln Ly #s Trp Leu Leu Ala                  95  #                100  #                105 Ala Gly Ala Gln Lys Cys His Ser Val Ile Th #r Gln Asp Phe Leu                 110   #               115   #               120 Thr Cys Trp Leu Ser Ile Arg Gln Ala Glu Le #u Leu Leu Pro Gly                 125   #               130   #               135 Ala Glu Phe His His Tyr Val Gly Gly Pro Th #r Glu Thr His Val                 140   #               145   #               150 Val Arg Ser Pro His Pro Tyr Gln Leu Pro Gl #n Ala Leu Ala Pro                 155   #               160   #               165 His Val Asp Phe Val Gly Gly Leu His Arg Ph #e Pro Pro Thr Ser                 170   #               175   #               180 Ser Leu Arg Gln Arg Pro Glu Pro Gln Val Th #r Gly Thr Val Gly                 185   #               190   #               195 Leu His Leu Gly Val Thr Pro Ser Val Ile Ar #g Lys Arg Tyr Asn                 200   #               205   #               210 Leu Thr Ser Gln Asp Val Gly Ser Gly Thr Se #r Asn Asn Ser Gln                 215   #               220   #               225 Ala Cys Ala Gln Phe Leu Glu Gln Tyr Phe Hi #s Asp Ser Asp Leu                 230   #               235   #               240 Ala Gln Phe Met Arg Leu Phe Gly Gly Asn Ph #e Ala His Gln Ala                 245   #               250   #               255 Ser Val Ala Arg Val Val Gly Gln Gln Gly Ar #g Gly Arg Ala Gly                 260   #               265   #               270 Ile Glu Ala Ser Leu Asp Val Gln Tyr Leu Me #t Ser Ala Gly Ala                 275   #               280   #               285 Asn Ile Ser Thr Trp Val Tyr Ser Ser Pro Gl #y Arg His Glu Gly                 290   #               295   #               300 Gln Glu Pro Phe Leu Gln Trp Leu Met Leu Le #u Ser Asn Glu Ser                 305   #               310   #               315 Ala Leu Pro His Val His Thr Val Ser Tyr Gl #y Asp Asp Glu Asp                 320   #               325   #               330 Ser Leu Ser Ser Ala Tyr Ile Gln Arg Val As #n Thr Glu Leu Met                 335   #               340   #               345 Lys Ala Ala Ala Arg Gly Leu Thr Leu Leu Ph #e Ala Ser Gly Asp                 350   #               355   #               360 Ser Gly Ala Gly Cys Trp Ser Val Ser Gly Ar #g His Gln Phe Arg                 365   #               370   #               375 Pro Thr Phe Pro Ala Ser Ser Pro Tyr Val Th #r Thr Val Gly Gly                 380   #               385   #               390 Thr Ser Phe Gln Glu Pro Phe Leu Ile Thr As #n Glu Ile Val Asp                 395   #               400   #               405 Tyr Ile Ser Gly Gly Gly Phe Ser Asn Val Ph #e Pro Arg Pro Ser                 410   #               415   #               420 Tyr Gln Glu Glu Ala Val Thr Lys Phe Leu Se #r Ser Ser Pro His                 425   #               430   #               435 Leu Pro Pro Ser Ser Tyr Phe Asn Ala Ser Gl #y Arg Ala Tyr Pro                 440   #               445   #               450 Asp Val Ala Ala Leu Ser Asp Gly Tyr Trp Va #l Val Ser Asn Arg                 455   #               460   #               465 Val Pro Ile Pro Trp Val Ser Gly Thr Ser Al #a Ser Thr Pro Val                 470   #               475   #               480 Phe Gly Gly Ile Leu Ser Leu Ile Asn Glu Hi #s Arg Ile Leu Ser                 485   #               490   #               495 Gly Arg Pro Pro Leu Gly Phe Leu Asn Pro Ar #g Leu Tyr Gln Gln                 500   #               505   #               510 His Gly Ala Gly Leu Phe Asp Val Thr Arg Gl #y Cys His Glu Ser                 515   #               520   #               525 Cys Leu Asp Glu Glu Val Glu Gly Gln Gly Ph #e Cys Ser Gly Pro                 530   #               535   #               540 Gly Trp Asp Pro Val Thr Gly Trp Gly Thr Pr #o Thr Ser Gln Leu                 545   #               550   #               555 Cys <210> SEQ ID NO 260 <211> LENGTH: 1638 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 260 gccgcgcgct ctctcccggc gcccacacct gtctgagcgg cgcagcgagc   #              50 cgcggcccgg gcgggctgct cggcgcggaa cagtgctcgg catggcaggg   #             100 attccagggc tcctcttcct tctcttcttt ctgctctgtg ctgttgggca   #             150 agtgagccct tacagtgccc cctggaaacc cacttggcct gcataccgcc   #             200 tccctgtcgt cttgccccag tctaccctca atttagccaa gccagacttt   #             250 ggagccgaag ccaaattaga agtatcttct tcatgtggac cccagtgtca   #             300 taagggaact ccactgccca cttacgaaga ggccaagcaa tatctgtctt   #             350 atgaaacgct ctatgccaat ggcagccgca cagagacgca ggtgggcatc   #             400 tacatcctca gcagtagtgg agatggggcc caacaccgag actcagggtc   #             450 ttcaggaaag tctcgaagga agcggcagat ttatggctat gacagcaggt   #             500 tcagcatttt tgggaaggac ttcctgctca actacccttt ctcaacatca   #             550 gtgaagttat ccacgggctg caccggcacc ctggtggcag agaagcatgt   #             600 cctcacagct gcccactgca tacacgatgg aaaaacctat gtgaaaggaa   #             650 cccagaagct tcgagtgggc ttcctaaagc ccaagtttaa agatggtggt   #             700 cgaggggcca acgactccac ttcagccatg cccgagcaga tgaaatttca   #             750 gtggatccgg gtgaaacgca cccatgtgcc caagggttgg atcaagggca   #             800 atgccaatga catcggcatg gattatgatt atgccctcct ggaactcaaa   #             850 aagccccaca agagaaaatt tatgaagatt ggggtgagcc ctcctgctaa   #             900 gcagctgcca gggggcagaa ttcacttctc tggttatgac aatgaccgac   #             950 caggcaattt ggtgtatcgc ttctgtgacg tcaaagacga gacctatgac   #            1000 ttgctctacc agcaatgcga tgcccagcca ggggccagcg ggtctggggt   #            1050 ctatgtgagg atgtggaaga gacagcagca gaagtgggag cgaaaaatta   #            1100 ttggcatttt ttcagggcac cagtgggtgg acatgaatgg ttccccacag   #            1150 gatttcaacg tggctgtcag aatcactcct ctcaaatatg cccagatttg   #            1200 ctattggatt aaaggaaact acctggattg tagggagggg tgacacagtg   #            1250 ttccctcctg gcagcaatta agggtcttca tgttcttatt ttaggagagg   #            1300 ccaaattgtt ttttgtcatt ggcgtgcaca cgtgtgtgtg tgtgtgtgtg   #            1350 tgtgtgtaag gtgtcttata atcttttacc tatttcttac aattgcaaga   #            1400 tgactggctt tactatttga aaactggttt gtgtatcata tcatatatca   #            1450 tttaagcagt ttgaaggcat acttttgcat agaaataaaa aaaatactga   #            1500 tttggggcaa tgaggaatat ttgacaatta agttaatctt cacgtttttg   #            1550 caaactttga tttttatttc atctgaactt gtttcaaaga tttatattaa   #            1600 atatttggca tacaagagat atgaaaaaaa aaaaaaaa       #                   #   1638 <210> SEQ ID NO 261 <211> LENGTH: 383 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 261 Met Ala Gly Ile Pro Gly Leu Leu Phe Leu Le #u Phe Phe Leu Leu   1               5  #                 10  #                 15 Cys Ala Val Gly Gln Val Ser Pro Tyr Ser Al #a Pro Trp Lys Pro                  20  #                 25  #                 30 Thr Trp Pro Ala Tyr Arg Leu Pro Val Val Le #u Pro Gln Ser Thr                  35  #                 40  #                 45 Leu Asn Leu Ala Lys Pro Asp Phe Gly Ala Gl #u Ala Lys Leu Glu                  50  #                 55  #                 60 Val Ser Ser Ser Cys Gly Pro Gln Cys His Ly #s Gly Thr Pro Leu                  65  #                 70  #                 75 Pro Thr Tyr Glu Glu Ala Lys Gln Tyr Leu Se #r Tyr Glu Thr Leu                  80  #                 85  #                 90 Tyr Ala Asn Gly Ser Arg Thr Glu Thr Gln Va #l Gly Ile Tyr Ile                  95  #                100  #                105 Leu Ser Ser Ser Gly Asp Gly Ala Gln His Ar #g Asp Ser Gly Ser                 110   #               115   #               120 Ser Gly Lys Ser Arg Arg Lys Arg Gln Ile Ty #r Gly Tyr Asp Ser                 125   #               130   #               135 Arg Phe Ser Ile Phe Gly Lys Asp Phe Leu Le #u Asn Tyr Pro Phe                 140   #               145   #               150 Ser Thr Ser Val Lys Leu Ser Thr Gly Cys Th #r Gly Thr Leu Val                 155   #               160   #               165 Ala Glu Lys His Val Leu Thr Ala Ala His Cy #s Ile His Asp Gly                 170   #               175   #               180 Lys Thr Tyr Val Lys Gly Thr Gln Lys Leu Ar #g Val Gly Phe Leu                 185   #               190   #               195 Lys Pro Lys Phe Lys Asp Gly Gly Arg Gly Al #a Asn Asp Ser Thr                 200   #               205   #               210 Ser Ala Met Pro Glu Gln Met Lys Phe Gln Tr #p Ile Arg Val Lys                 215   #               220   #               225 Arg Thr His Val Pro Lys Gly Trp Ile Lys Gl #y Asn Ala Asn Asp                 230   #               235   #               240 Ile Gly Met Asp Tyr Asp Tyr Ala Leu Leu Gl #u Leu Lys Lys Pro                 245   #               250   #               255 His Lys Arg Lys Phe Met Lys Ile Gly Val Se #r Pro Pro Ala Lys                 260   #               265   #               270 Gln Leu Pro Gly Gly Arg Ile His Phe Ser Gl #y Tyr Asp Asn Asp                 275   #               280   #               285 Arg Pro Gly Asn Leu Val Tyr Arg Phe Cys As #p Val Lys Asp Glu                 290   #               295   #               300 Thr Tyr Asp Leu Leu Tyr Gln Gln Cys Asp Al #a Gln Pro Gly Ala                 305   #               310   #               315 Ser Gly Ser Gly Val Tyr Val Arg Met Trp Ly #s Arg Gln Gln Gln                 320   #               325   #               330 Lys Trp Glu Arg Lys Ile Ile Gly Ile Phe Se #r Gly His Gln Trp                 335   #               340   #               345 Val Asp Met Asn Gly Ser Pro Gln Asp Phe As #n Val Ala Val Arg                 350   #               355   #               360 Ile Thr Pro Leu Lys Tyr Ala Gln Ile Cys Ty #r Trp Ile Lys Gly                 365   #               370   #               375 Asn Tyr Leu Asp Cys Arg Glu Gly                 380 <210> SEQ ID NO 262 <211> LENGTH: 1378 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 262 gcatcgccct gggtctctcg agcctgctgc ctgctccccc gccccaccag   #              50 ccatggtggt ttctggagcg cccccagccc tgggtggggg ctgtctcggc   #             100 accttcacct ccctgctgct gctggcgtcg acagccatcc tcaatgcggc   #             150 caggatacct gttcccccag cctgtgggaa gccccagcag ctgaaccggg   #             200 ttgtgggcgg cgaggacagc actgacagcg agtggccctg gatcgtgagc   #             250 atccagaaga atgggaccca ccactgcgca ggttctctgc tcaccagccg   #             300 ctgggtgatc actgctgccc actgtttcaa ggacaacctg aacaaaccat   #             350 acctgttctc tgtgctgctg ggggcctggc agctggggaa ccctggctct   #             400 cggtcccaga aggtgggtgt tgcctgggtg gagccccacc ctgtgtattc   #             450 ctggaaggaa ggtgcctgtg cagacattgc cctggtgcgt ctcgagcgct   #             500 ccatacagtt ctcagagcgg gtcctgccca tctgcctacc tgatgcctct   #             550 atccacctcc ctccaaacac ccactgctgg atctcaggct gggggagcat   #             600 ccaagatgga gttcccttgc cccaccctca gaccctgcag aagctgaagg   #             650 ttcctatcat cgactcggaa gtctgcagcc atctgtactg gcggggagca   #             700 ggacagggac ccatcactga ggacatgctg tgtgccggct acttggaggg   #             750 ggagcgggat gcttgtctgg gcgactccgg gggccccctc atgtgccagg   #             800 tggacggcgc ctggctgctg gccggcatca tcagctgggg cgagggctgt   #             850 gccgagcgca acaggcccgg ggtctacatc agcctctctg cgcaccgctc   #             900 ctgggtggag aagatcgtgc aaggggtgca gctccgcggg cgcgctcagg   #             950 ggggtggggc cctcagggca ccgagccagg gctctggggc cgccgcgcgc   #            1000 tcctagggcg cagcgggacg cggggctcgg atctgaaagg cggccagatc   #            1050 cacatctgga tctggatctg cggcggcctc gggcggtttc ccccgccgta   #            1100 aataggctca tctacctcta cctctggggg cccggacggc tgctgcggaa   #            1150 aggaaacccc ctccccgacc cgcccgacgg cctcaggccc ccctccaagg   #            1200 catcaggccc cgcccaacgg cctcatgtcc ccgcccccac gacttccggc   #            1250 cccgcccccg ggccccagcg cttttgtgta tataaatgtt aatgattttt   #            1300 ataggtattt gtaaccctgc ccacatatct tatttattcc tccaatttca   #            1350 ataaattatt tattctccaa aaaaaaaa          #                   #           1378 <210> SEQ ID NO 263 <211> LENGTH: 317 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 263 Met Val Val Ser Gly Ala Pro Pro Ala Leu Gl #y Gly Gly Cys Leu   1               5  #                 10  #                 15 Gly Thr Phe Thr Ser Leu Leu Leu Leu Ala Se #r Thr Ala Ile Leu                  20  #                 25  #                 30 Asn Ala Ala Arg Ile Pro Val Pro Pro Ala Cy #s Gly Lys Pro Gln                  35  #                 40  #                 45 Gln Leu Asn Arg Val Val Gly Gly Glu Asp Se #r Thr Asp Ser Glu                  50  #                 55  #                 60 Trp Pro Trp Ile Val Ser Ile Gln Lys Asn Gl #y Thr His His Cys                  65  #                 70  #                 75 Ala Gly Ser Leu Leu Thr Ser Arg Trp Val Il #e Thr Ala Ala His                  80  #                 85  #                 90 Cys Phe Lys Asp Asn Leu Asn Lys Pro Tyr Le #u Phe Ser Val Leu                  95  #                100  #                105 Leu Gly Ala Trp Gln Leu Gly Asn Pro Gly Se #r Arg Ser Gln Lys                 110   #               115   #               120 Val Gly Val Ala Trp Val Glu Pro His Pro Va #l Tyr Ser Trp Lys                 125   #               130   #               135 Glu Gly Ala Cys Ala Asp Ile Ala Leu Val Ar #g Leu Glu Arg Ser                 140   #               145   #               150 Ile Gln Phe Ser Glu Arg Val Leu Pro Ile Cy #s Leu Pro Asp Ala                 155   #               160   #               165 Ser Ile His Leu Pro Pro Asn Thr His Cys Tr #p Ile Ser Gly Trp                 170   #               175   #               180 Gly Ser Ile Gln Asp Gly Val Pro Leu Pro Hi #s Pro Gln Thr Leu                 185   #               190   #               195 Gln Lys Leu Lys Val Pro Ile Ile Asp Ser Gl #u Val Cys Ser His                 200   #               205   #               210 Leu Tyr Trp Arg Gly Ala Gly Gln Gly Pro Il #e Thr Glu Asp Met                 215   #               220   #               225 Leu Cys Ala Gly Tyr Leu Glu Gly Glu Arg As #p Ala Cys Leu Gly                 230   #               235   #               240 Asp Ser Gly Gly Pro Leu Met Cys Gln Val As #p Gly Ala Trp Leu                 245   #               250   #               255 Leu Ala Gly Ile Ile Ser Trp Gly Glu Gly Cy #s Ala Glu Arg Asn                 260   #               265   #               270 Arg Pro Gly Val Tyr Ile Ser Leu Ser Ala Hi #s Arg Ser Trp Val                 275   #               280   #               285 Glu Lys Ile Val Gln Gly Val Gln Leu Arg Gl #y Arg Ala Gln Gly                 290   #               295   #               300 Gly Gly Ala Leu Arg Ala Pro Ser Gln Gly Se #r Gly Ala Ala Ala                 305   #               310   #               315 Arg Ser <210> SEQ ID NO 264 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 264 gtccgcaagg atgcctacat gttc           #                   #                24 <210> SEQ ID NO 265 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 265 gcagaggtgt ctaaggttg              #                   #                   # 19 <210> SEQ ID NO 266 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 266 agctctagac caatgccagc ttcc           #                   #                24 <210> SEQ ID NO 267 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 267 gccaccaact cctgcaagaa cttctcagaa ctgcccctgg tcatg    #                   #45 <210> SEQ ID NO 268 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 268 ggggaattca ccctatgaca ttgcc           #                   #               25 <210> SEQ ID NO 269 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 269 gaatgccctg caagcatcaa ctgg           #                   #                24 <210> SEQ ID NO 270 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 270 gcacctgtca cctacactaa acacatccag cccatctgtc tccaggcctc   #              50 <210> SEQ ID NO 271 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 271 gcggaagggc agaatgggac tccaag           #                   #              26 <210> SEQ ID NO 272 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 272 cagccctgcc acatgtgc              #                   #                   #  18 <210> SEQ ID NO 273 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 273 tactgggtgg tcagcaac              #                   #                   #  18 <210> SEQ ID NO 274 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 274 ggcgaagagc agggtgagac cccg           #                   #               24 <210> SEQ ID NO 275 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 275 gccctcatcc tctctggcaa atgcagttac agcccggagc ccgac    #                   #45 <210> SEQ ID NO 276 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 276 gggcagggat tccagggctc c            #                   #                   #21 <210> SEQ ID NO 277 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 277 ggctatgaca gcaggttc              #                   #                   #  18 <210> SEQ ID NO 278 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 278 tgacaatgac cgaccagg              #                   #                   #  18 <210> SEQ ID NO 279 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 279 gcatcgcatt gctggtagag caag           #                   #               24 <210> SEQ ID NO 280 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 280 ttacagtgcc ccctggaaac ccacttggcc tgcataccgc ctccc    #                   #45 <210> SEQ ID NO 281 <211> LENGTH: 34 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 281 cgtctcgagc gctccataca gttcccttgc ccca        #                   #        34 <210> SEQ ID NO 282 <211> LENGTH: 61 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 282 tggaggggga gcgggatgct tgtctgggcg actccggggg ccccctcatg   #              50 tgccaggtgg a                #                   #                   #       61 <210> SEQ ID NO 283 <211> LENGTH: 119 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 283 ccctcagacc ctgcagaagc tgaaggttcc tatcatcgac tcggaagtct   #              50 gcagccatct gtactggcgg ggagcaggac agggacccat cactgaggac   #             100 atgctgtgtg ccggctact              #                   #                   #119 <210> SEQ ID NO 284 <211> LENGTH: 1875 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 284 gacggctggc caccatgcac ggctcctgca gtttcctgat gcttctgctg   #              50 ccgctactgc tactgctggt ggccaccaca ggccccgttg gagccctcac   #             100 agatgaggag aaacgtttga tggtggagct gcacaacctc taccgggccc   #             150 aggtatcccc gacggcctca gacatgctgc acatgagatg ggacgaggag   #             200 ctggccgcct tcgccaaggc ctacgcacgg cagtgcgtgt ggggccacaa   #             250 caaggagcgc gggcgccgcg gcgagaatct gttcgccatc acagacgagg   #             300 gcatggacgt gccgctggcc atggaggagt ggcaccacga gcgtgagcac   #             350 tacaacctca gcgccgccac ctgcagccca ggccagatgt gcggccacta   #             400 cacgcaggtg gtatgggcca agacagagag gatcggctgt ggttcccact   #             450 tctgtgagaa gctccagggt gttgaggaga ccaacatcga attactggtg   #             500 tgcaactatg agcctccggg gaacgtgaag gggaaacggc cctaccagga   #             550 ggggactccg tgctcccaat gtccctctgg ctaccactgc aagaactccc   #             600 tctgtgaacc catcggaagc ccggaagatg ctcaggattt gccttacctg   #             650 gtaactgagg ccccatcctt ccgggcgact gaagcatcag actctaggaa   #             700 aatgggtact ccttcttccc tagcaacggg gattccggct ttcttggtaa   #             750 cagaggtctc aggctccctg gcaaccaagg ctctgcctgc tgtggaaacc   #             800 caggccccaa cttccttagc aacgaaagac ccgccctcca tggcaacaga   #             850 ggctccacct tgcgtaacaa ctgaggtccc ttccattttg gcagctcaca   #             900 gcctgccctc cttggatgag gagccagtta ccttccccaa atcgacccat   #             950 gttcctatcc caaaatcagc agacaaagtg acagacaaaa caaaagtgcc   #            1000 ctctaggagc ccagagaact ctctggaccc caagatgtcc ctgacagggg   #            1050 caagggaact cctaccccat gcccaggagg aggctgaggc tgaggctgag   #            1100 ttgcctcctt ccagtgaggt cttggcctca gtttttccag cccaggacaa   #            1150 gccaggtgag ctgcaggcca cactggacca cacggggcac acctcctcca   #            1200 agtccctgcc caatttcccc aatacctctg ccaccgctaa tgccacgggt   #            1250 gggcgtgccc tggctctgca gtcgtccttg ccaggtgcag agggccctga   #            1300 caagcctagc gttgtgtcag ggctgaactc gggccctggt catgtgtggg   #            1350 gccctctcct gggactactg ctcctgcctc ctctggtgtt ggctggaatc   #            1400 ttctgaatgg gataccactc aaagggtgaa gaggtcagct gtcctcctgt   #            1450 catcttcccc accctgtccc cagcccctaa acaagatact tcttggttaa   #            1500 ggccctccgg aagggaaagg ctacggggca tgtgcctcat cacaccatcc   #            1550 atcctggagg cacaaggcct ggctggctgc gagctcagga ggccgcctga   #            1600 ggactgcaca ccgggcccac acctctcctg cccctccctc ctgagtcctg   #            1650 ggggtgggag gatttgaggg agctcactgc ctacctggcc tggggctgtc   #            1700 tgcccacaca gcatgtgcgc tctccctgag tgcctgtgta gctggggatg   #            1750 gggattccta ggggcagatg aaggacaagc cccactggag tggggttctt   #            1800 tgagtggggg aggcagggac gagggaagga aagtaactcc tgactctcca   #            1850 ataaaaacct gtccaacctg tgaaa           #                   #             1875 <210> SEQ ID NO 285 <211> LENGTH: 463 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 285 Met His Gly Ser Cys Ser Phe Leu Met Leu Le #u Leu Pro Leu Leu   1               5  #                 10  #                 15 Leu Leu Leu Val Ala Thr Thr Gly Pro Val Gl #y Ala Leu Thr Asp                  20  #                 25  #                 30 Glu Glu Lys Arg Leu Met Val Glu Leu His As #n Leu Tyr Arg Ala                  35  #                 40  #                 45 Gln Val Ser Pro Thr Ala Ser Asp Met Leu Hi #s Met Arg Trp Asp                  50  #                 55  #                 60 Glu Glu Leu Ala Ala Phe Ala Lys Ala Tyr Al #a Arg Gln Cys Val                  65  #                 70  #                 75 Trp Gly His Asn Lys Glu Arg Gly Arg Arg Gl #y Glu Asn Leu Phe                  80  #                 85  #                 90 Ala Ile Thr Asp Glu Gly Met Asp Val Pro Le #u Ala Met Glu Glu                  95  #                100  #                105 Trp His His Glu Arg Glu His Tyr Asn Leu Se #r Ala Ala Thr Cys                 110   #               115   #               120 Ser Pro Gly Gln Met Cys Gly His Tyr Thr Gl #n Val Val Trp Ala                 125   #               130   #               135 Lys Thr Glu Arg Ile Gly Cys Gly Ser His Ph #e Cys Glu Lys Leu                 140   #               145   #               150 Gln Gly Val Glu Glu Thr Asn Ile Glu Leu Le #u Val Cys Asn Tyr                 155   #               160   #               165 Glu Pro Pro Gly Asn Val Lys Gly Lys Arg Pr #o Tyr Gln Glu Gly                 170   #               175   #               180 Thr Pro Cys Ser Gln Cys Pro Ser Gly Tyr Hi #s Cys Lys Asn Ser                 185   #               190   #               195 Leu Cys Glu Pro Ile Gly Ser Pro Glu Asp Al #a Gln Asp Leu Pro                 200   #               205   #               210 Tyr Leu Val Thr Glu Ala Pro Ser Phe Arg Al #a Thr Glu Ala Ser                 215   #               220   #               225 Asp Ser Arg Lys Met Gly Thr Pro Ser Ser Le #u Ala Thr Gly Ile                 230   #               235   #               240 Pro Ala Phe Leu Val Thr Glu Val Ser Gly Se #r Leu Ala Thr Lys                 245   #               250   #               255 Ala Leu Pro Ala Val Glu Thr Gln Ala Pro Th #r Ser Leu Ala Thr                 260   #               265   #               270 Lys Asp Pro Pro Ser Met Ala Thr Glu Ala Pr #o Pro Cys Val Thr                 275   #               280   #               285 Thr Glu Val Pro Ser Ile Leu Ala Ala His Se #r Leu Pro Ser Leu                 290   #               295   #               300 Asp Glu Glu Pro Val Thr Phe Pro Lys Ser Th #r His Val Pro Ile                 305   #               310   #               315 Pro Lys Ser Ala Asp Lys Val Thr Asp Lys Th #r Lys Val Pro Ser                 320   #               325   #               330 Arg Ser Pro Glu Asn Ser Leu Asp Pro Lys Me #t Ser Leu Thr Gly                 335   #               340   #               345 Ala Arg Glu Leu Leu Pro His Ala Gln Glu Gl #u Ala Glu Ala Glu                 350   #               355   #               360 Ala Glu Leu Pro Pro Ser Ser Glu Val Leu Al #a Ser Val Phe Pro                 365   #               370   #               375 Ala Gln Asp Lys Pro Gly Glu Leu Gln Ala Th #r Leu Asp His Thr                 380   #               385   #               390 Gly His Thr Ser Ser Lys Ser Leu Pro Asn Ph #e Pro Asn Thr Ser                 395   #               400   #               405 Ala Thr Ala Asn Ala Thr Gly Gly Arg Ala Le #u Ala Leu Gln Ser                 410   #               415   #               420 Ser Leu Pro Gly Ala Glu Gly Pro Asp Lys Pr #o Ser Val Val Ser                 425   #               430   #               435 Gly Leu Asn Ser Gly Pro Gly His Val Trp Gl #y Pro Leu Leu Gly                 440   #               445   #               450 Leu Leu Leu Leu Pro Pro Leu Val Leu Ala Gl #y Ile Phe                 455   #               460 <210> SEQ ID NO 286 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 286 tcctgcagtt tcctgatgc              #                   #                   # 19 <210> SEQ ID NO 287 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 287 ctcatattgc acaccagtaa ttcg           #                   #                24 <210> SEQ ID NO 288 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 288 atgaggagaa acgtttgatg gtggagctgc acaacctcta ccggg    #                   #45 <210> SEQ ID NO 289 <211> LENGTH: 3662 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 289 gtaactgaag tcaggctttt catttgggaa gccccctcaa cagaattcgg   #              50 tcattctcca agttatggtg gacgtacttc tgttgttctc cctctgcttg   #             100 ctttttcaca ttagcagacc ggacttaagt cacaacagat tatctttcat   #             150 caaggcaagt tccatgagcc accttcaaag ccttcgagaa gtgaaactga   #             200 acaacaatga attggagacc attccaaatc tgggaccagt ctcggcaaat   #             250 attacacttc tctccttggc tggaaacagg attgttgaaa tactccctga   #             300 acatctgaaa gagtttcagt cccttgaaac tttggacctt agcagcaaca   #             350 atatttcaga gctccaaact gcatttccag ccctacagct caaatatctg   #             400 tatctcaaca gcaaccgagt cacatcaatg gaacctgggt attttgacaa   #             450 tttggccaac acactccttg tgttaaagct gaacaggaac cgaatctcag   #             500 ctatcccacc caagatgttt aaactgcccc aactgcaaca tctcgaattg   #             550 aaccgaaaca agattaaaaa tgtagatgga ctgacattcc aaggccttgg   #             600 tgctctgaag tctctgaaaa tgcaaagaaa tggagtaacg aaacttatgg   #             650 atggagcttt ttgggggctg agcaacatgg aaattttgca gctggaccat   #             700 aacaacctaa cagagattac caaaggctgg ctttacggct tgctgatgct   #             750 gcaggaactt catctcagcc aaaatgccat caacaggatc agccctgatg   #             800 cctgggagtt ctgccagaag ctcagtgagc tggacctaac tttcaatcac   #             850 ttatcaaggt tagatgattc aagcttcctt ggcctaagct tactaaatac   #             900 actgcacatt gggaacaaca gagtcagcta cattgctgat tgtgccttcc   #             950 gggggctttc cagtttaaag actttggatc tgaagaacaa tgaaatttcc   #            1000 tggactattg aagacatgaa tggtgctttc tctgggcttg acaaactgag   #            1050 gcgactgata ctccaaggaa atcggatccg ttctattact aaaaaagcct   #            1100 tcactggttt ggatgcattg gagcatctag acctgagtga caacgcaatc   #            1150 atgtctttac aaggcaatgc attttcacaa atgaagaaac tgcaacaatt   #            1200 gcatttaaat acatcaagcc ttttgtgcga ttgccagcta aaatggctcc   #            1250 cacagtgggt ggcggaaaac aactttcaga gctttgtaaa tgccagttgt   #            1300 gcccatcctc agctgctaaa aggaagaagc atttttgctg ttagcccaga   #            1350 tggctttgtg tgtgatgatt ttcccaaacc ccagatcacg gttcagccag   #            1400 aaacacagtc ggcaataaaa ggttccaatt tgagtttcat ctgctcagct   #            1450 gccagcagca gtgattcccc aatgactttt gcttggaaaa aagacaatga   #            1500 actactgcat gatgctgaaa tggaaaatta tgcacacctc cgggcccaag   #            1550 gtggcgaggt gatggagtat accaccatcc ttcggctgcg cgaggtggaa   #            1600 tttgccagtg aggggaaata tcagtgtgtc atctccaatc actttggttc   #            1650 atcctactct gtcaaagcca agcttacagt aaatatgctt ccctcattca   #            1700 ccaagacccc catggatctc accatccgag ctggggccat ggcacgcttg   #            1750 gagtgtgctg ctgtggggca cccagccccc cagatagcct ggcagaagga   #            1800 tgggggcaca gacttcccag ctgcacggga gagacgcatg catgtgatgc   #            1850 ccgaggatga cgtgttcttt atcgtggatg tgaagataga ggacattggg   #            1900 gtatacagct gcacagctca gaacagtgca ggaagtattt cagcaaatgc   #            1950 aactctgact gtcctagaaa caccatcatt tttgcggcca ctgttggacc   #            2000 gaactgtaac caagggagaa acagccgtcc tacagtgcat tgctggagga   #            2050 agccctcccc ctaaactgaa ctggaccaaa gatgatagcc cattggtggt   #            2100 aaccgagagg cacttttttg cagcaggcaa tcagcttctg attattgtgg   #            2150 actcagatgt cagtgatgct gggaaataca catgtgagat gtctaacacc   #            2200 cttggcactg agagaggaaa cgtgcgcctc agtgtgatcc ccactccaac   #            2250 ctgcgactcc cctcagatga cagccccatc gttagacgat gacggatggg   #            2300 ccactgtggg tgtcgtgatc atagccgtgg tttgctgtgt ggtgggcacg   #            2350 tcactcgtgt gggtggtcat catataccac acaaggcgga ggaatgaaga   #            2400 ttgcagcatt accaacacag atgagaccaa cttgccagca gatattccta   #            2450 gttatttgtc atctcaggga acgttagctg acaggcagga tgggtacgtg   #            2500 tcttcagaaa gtggaagcca ccaccagttt gtcacatctt caggtgctgg   #            2550 atttttctta ccacaacatg acagtagtgg gacctgccat attgacaata   #            2600 gcagtgaagc tgatgtggaa gctgccacag atctgttcct ttgtccgttt   #            2650 ttgggatcca caggccctat gtatttgaag ggaaatgtgt atggctcaga   #            2700 tccttttgaa acatatcata caggttgcag tcctgaccca agaacagttt   #            2750 taatggacca ctatgagccc agttacataa agaaaaagga gtgctaccca   #            2800 tgttctcatc cttcagaaga atcctgcgaa cggagcttca gtaatatatc   #            2850 gtggccttca catgtgagga agctacttaa cactagttac tctcacaatg   #            2900 aaggacctgg aatgaaaaat ctgtgtctaa acaagtcctc tttagatttt   #            2950 agtgcaaatc cagagccagc gtcggttgcc tcgagtaatt ctttcatggg   #            3000 tacctttgga aaagctctca ggagacctca cctagatgcc tattcaagct   #            3050 ttggacagcc atcagattgt cagccaagag ccttttattt gaaagctcat   #            3100 tcttccccag acttggactc tgggtcagag gaagatggga aagaaaggac   #            3150 agattttcag gaagaaaatc acatttgtac ctttaaacag actttagaaa   #            3200 actacaggac tccaaatttt cagtcttatg acttggacac atagactgaa   #            3250 tgagaccaaa ggaaaagctt aacatactac ctcaagtgaa cttttattta   #            3300 aaagagagag aatcttatgt tttttaaatg gagttatgaa ttttaaaagg   #            3350 ataaaaatgc tttatttata cagatgaacc aaaattacaa aaagttatga   #            3400 aaatttttat actgggaatg atgctcatat aagaatacct ttttaaacta   #            3450 ttttttaact ttgttttatg caaaaaagta tcttacgtaa attaatgata   #            3500 taaatcatga ttattttatg tatttttata atgccagatt tctttttatg   #            3550 gaaaatgagt tactaaagca ttttaaataa tacctgcctt gtaccatttt   #            3600 ttaaatagaa gttacttcat tatattttgc acattatatt taataaaatg   #            3650 tgtcaatttg aa               #                   #                   #     3662 <210> SEQ ID NO 290 <211> LENGTH: 1059 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 290 Met Val Asp Val Leu Leu Leu Phe Ser Leu Cy #s Leu Leu Phe His   1               5  #                 10  #                 15 Ile Ser Arg Pro Asp Leu Ser His Asn Arg Le #u Ser Phe Ile Lys                  20  #                 25  #                 30 Ala Ser Ser Met Ser His Leu Gln Ser Leu Ar #g Glu Val Lys Leu                  35  #                 40  #                 45 Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Le #u Gly Pro Val Ser                  50  #                 55  #                 60 Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly As #n Arg Ile Val Glu                  65  #                 70  #                 75 Ile Leu Pro Glu His Leu Lys Glu Phe Gln Se #r Leu Glu Thr Leu                  80  #                 85  #                 90 Asp Leu Ser Ser Asn Asn Ile Ser Glu Leu Gl #n Thr Ala Phe Pro                  95  #                100  #                105 Ala Leu Gln Leu Lys Tyr Leu Tyr Leu Asn Se #r Asn Arg Val Thr                 110   #               115   #               120 Ser Met Glu Pro Gly Tyr Phe Asp Asn Leu Al #a Asn Thr Leu Leu                 125   #               130   #               135 Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Al #a Ile Pro Pro Lys                 140   #               145   #               150 Met Phe Lys Leu Pro Gln Leu Gln His Leu Gl #u Leu Asn Arg Asn                 155   #               160   #               165 Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gl #n Gly Leu Gly Ala                 170   #               175   #               180 Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Va #l Thr Lys Leu Met                 185   #               190   #               195 Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Gl #u Ile Leu Gln Leu                 200   #               205   #               210 Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gl #y Trp Leu Tyr Gly                 215   #               220   #               225 Leu Leu Met Leu Gln Glu Leu His Leu Ser Gl #n Asn Ala Ile Asn                 230   #               235   #               240 Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gl #n Lys Leu Ser Glu                 245   #               250   #               255 Leu Asp Leu Thr Phe Asn His Leu Ser Arg Le #u Asp Asp Ser Ser                 260   #               265   #               270 Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu Hi #s Ile Gly Asn Asn                 275   #               280   #               285 Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Ar #g Gly Leu Ser Ser                 290   #               295   #               300 Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Il #e Ser Trp Thr Ile                 305   #               310   #               315 Glu Asp Met Asn Gly Ala Phe Ser Gly Leu As #p Lys Leu Arg Arg                 320   #               325   #               330 Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser Il #e Thr Lys Lys Ala                 335   #               340   #               345 Phe Thr Gly Leu Asp Ala Leu Glu His Leu As #p Leu Ser Asp Asn                 350   #               355   #               360 Ala Ile Met Ser Leu Gln Gly Asn Ala Phe Se #r Gln Met Lys Lys                 365   #               370   #               375 Leu Gln Gln Leu His Leu Asn Thr Ser Ser Le #u Leu Cys Asp Cys                 380   #               385   #               390 Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Gl #u Asn Asn Phe Gln                 395   #               400   #               405 Ser Phe Val Asn Ala Ser Cys Ala His Pro Gl #n Leu Leu Lys Gly                 410   #               415   #               420 Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Ph #e Val Cys Asp Asp                 425   #               430   #               435 Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Gl #u Thr Gln Ser Ala                 440   #               445   #               450 Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Se #r Ala Ala Ser Ser                 455   #               460   #               465 Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Ly #s Asp Asn Glu Leu                 470   #               475   #               480 Leu His Asp Ala Glu Met Glu Asn Tyr Ala Hi #s Leu Arg Ala Gln                 485   #               490   #               495 Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Le #u Arg Leu Arg Glu                 500   #               505   #               510 Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cy #s Val Ile Ser Asn                 515   #               520   #               525 His Phe Gly Ser Ser Tyr Ser Val Lys Ala Ly #s Leu Thr Val Asn                 530   #               535   #               540 Met Leu Pro Ser Phe Thr Lys Thr Pro Met As #p Leu Thr Ile Arg                 545   #               550   #               555 Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Al #a Val Gly His Pro                 560   #               565   #               570 Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gl #y Thr Asp Phe Pro                 575   #               580   #               585 Ala Ala Arg Glu Arg Arg Met His Val Met Pr #o Glu Asp Asp Val                 590   #               595   #               600 Phe Phe Ile Val Asp Val Lys Ile Glu Asp Il #e Gly Val Tyr Ser                 605   #               610   #               615 Cys Thr Ala Gln Asn Ser Ala Gly Ser Ile Se #r Ala Asn Ala Thr                 620   #               625   #               630 Leu Thr Val Leu Glu Thr Pro Ser Phe Leu Ar #g Pro Leu Leu Asp                 635   #               640   #               645 Arg Thr Val Thr Lys Gly Glu Thr Ala Val Le #u Gln Cys Ile Ala                 650   #               655   #               660 Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Th #r Lys Asp Asp Ser                 665   #               670   #               675 Pro Leu Val Val Thr Glu Arg His Phe Phe Al #a Ala Gly Asn Gln                 680   #               685   #               690 Leu Leu Ile Ile Val Asp Ser Asp Val Ser As #p Ala Gly Lys Tyr                 695   #               700   #               705 Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Gl #u Arg Gly Asn Val                 710   #               715   #               720 Arg Leu Ser Val Ile Pro Thr Pro Thr Cys As #p Ser Pro Gln Met                 725   #               730   #               735 Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp Al #a Thr Val Gly Val                 740   #               745   #               750 Val Ile Ile Ala Val Val Cys Cys Val Val Gl #y Thr Ser Leu Val                 755   #               760   #               765 Trp Val Val Ile Ile Tyr His Thr Arg Arg Ar #g Asn Glu Asp Cys                 770   #               775   #               780 Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pr #o Ala Asp Ile Pro                 785   #               790   #               795 Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala As #p Arg Gln Asp Gly                 800   #               805   #               810 Tyr Val Ser Ser Glu Ser Gly Ser His His Gl #n Phe Val Thr Ser                 815   #               820   #               825 Ser Gly Ala Gly Phe Phe Leu Pro Gln His As #p Ser Ser Gly Thr                 830   #               835   #               840 Cys His Ile Asp Asn Ser Ser Glu Ala Asp Va #l Glu Ala Ala Thr                 845   #               850   #               855 Asp Leu Phe Leu Cys Pro Phe Leu Gly Ser Th #r Gly Pro Met Tyr                 860   #               865   #               870 Leu Lys Gly Asn Val Tyr Gly Ser Asp Pro Ph #e Glu Thr Tyr His                 875   #               880   #               885 Thr Gly Cys Ser Pro Asp Pro Arg Thr Val Le #u Met Asp His Tyr                 890   #               895   #               900 Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Ty #r Pro Cys Ser His                 905   #               910   #               915 Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Se #r Asn Ile Ser Trp                 920   #               925   #               930 Pro Ser His Val Arg Lys Leu Leu Asn Thr Se #r Tyr Ser His Asn                 935   #               940   #               945 Glu Gly Pro Gly Met Lys Asn Leu Cys Leu As #n Lys Ser Ser Leu                 950   #               955   #               960 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Va #l Ala Ser Ser Asn                 965   #               970   #               975 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Ar #g Arg Pro His Leu                 980   #               985   #               990 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser As #p Cys Gln Pro Arg                 995   #              1000    #             1005 Ala Phe Tyr Leu Lys Ala His Ser Ser Pro As #p Leu Asp Ser Gly                1010   #              1015    #             1020 Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Ph #e Gln Glu Glu Asn                1025   #              1030    #             1035 His Ile Cys Thr Phe Lys Gln Thr Leu Glu As #n Tyr Arg Thr Pro                1040   #              1045    #             1050 Asn Phe Gln Ser Tyr Asp Leu Asp Thr                1055 <210> SEQ ID NO 291 <211> LENGTH: 2906 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 291 ggggagagga attgaccatg taaaaggaga cttttttttt tggtggtggt   #              50 ggctgttggg tgccttgcaa aaatgaagga tgcaggacgc agctttctcc   #             100 tggaaccgaa cgcaatggat aaactgattg tgcaagagag aaggaagaac   #             150 gaagcttttt cttgtgagcc ctggatctta acacaaatgt gtatatgtgc   #             200 acacagggag cattcaagaa tgaaataaac cagagttaga cccgcggggg   #             250 ttggtgtgtt ctgacataaa taaataatct taaagcagct gttcccctcc   #             300 ccacccccaa aaaaaaggat gattggaaat gaagaaccga ggattcacaa   #             350 agaaaaaagt atgttcattt ttctctataa aggagaaagt gagccaagga   #             400 gatatttttg gaatgaaaag tttggggctt ttttagtaaa gtaaagaact   #             450 ggtgtggtgg tgttttcctt tctttttgaa tttcccacaa gaggagagga   #             500 aattaataat acatctgcaa agaaatttca gagaagaaaa gttgaccgcg   #             550 gcagattgag gcattgattg ggggagagaa accagcagag cacagttgga   #             600 tttgtgccta tgttgactaa aattgacgga taattgcagt tggatttttc   #             650 ttcatcaacc tccttttttt taaattttta ttccttttgg tatcaagatc   #             700 atgcgttttc tcttgttctt aaccacctgg atttccatct ggatgttgct   #             750 gtgatcagtc tgaaatacaa ctgtttgaat tccagaagga ccaacaccag   #             800 ataaattatg aatgttgaac aagatgacct tacatccaca gcagataatg   #             850 ataggtccta ggtttaacag ggccctattt gaccccctgc ttgtggtgct   #             900 gctggctctt caacttcttg tggtggctgg tctggtgcgg gctcagacct   #             950 gcccttctgt gtgctcctgc agcaaccagt tcagcaaggt gatttgtgtt   #            1000 cggaaaaacc tgcgtgaggt tccggatggc atctccacca acacacggct   #            1050 gctgaacctc catgagaacc aaatccagat catcaaagtg aacagcttca   #            1100 agcacttgag gcacttggaa atcctacagt tgagtaggaa ccatatcaga   #            1150 accattgaaa ttggggcttt caatggtctg gcgaacctca acactctgga   #            1200 actctttgac aatcgtctta ctaccatccc gaatggagct tttgtatact   #            1250 tgtctaaact gaaggagctc tggttgcgaa acaaccccat tgaaagcatc   #            1300 ccttcttatg cttttaacag aattccttct ttgcgccgac tagacttagg   #            1350 ggaattgaaa agactttcat acatctcaga aggtgccttt gaaggtctgt   #            1400 ccaacttgag gtatttgaac cttgccatgt gcaaccttcg ggaaatccct   #            1450 aacctcacac cgctcataaa actagatgag ctggatcttt ctgggaatca   #            1500 tttatctgcc atcaggcctg gctctttcca gggtttgatg caccttcaaa   #            1550 aactgtggat gatacagtcc cagattcaag tgattgaacg gaatgccttt   #            1600 gacaaccttc agtcactagt ggagatcaac ctggcacaca ataatctaac   #            1650 attactgcct catgacctct tcactccctt gcatcatcta gagcggatac   #            1700 atttacatca caacccttgg aactgtaact gtgacatact gtggctcagc   #            1750 tggtggataa aagacatggc cccctcgaac acagcttgtt gtgcccggtg   #            1800 taacactcct cccaatctaa aggggaggta cattggagag ctcgaccaga   #            1850 attacttcac atgctatgct ccggtgattg tggagccccc tgcagacctc   #            1900 aatgtcactg aaggcatggc agctgagctg aaatgtcggg cctccacatc   #            1950 cctgacatct gtatcttgga ttactccaaa tggaacagtc atgacacatg   #            2000 gggcgtacaa agtgcggata gctgtgctca gtgatggtac gttaaatttc   #            2050 acaaatgtaa ctgtgcaaga tacaggcatg tacacatgta tggtgagtaa   #            2100 ttccgttggg aatactactg cttcagccac cctgaatgtt actgcagcaa   #            2150 ccactactcc tttctcttac ttttcaaccg tcacagtaga gactatggaa   #            2200 ccgtctcagg atgaggcacg gaccacagat aacaatgtgg gtcccactcc   #            2250 agtggtcgac tgggagacca ccaatgtgac cacctctctc acaccacaga   #            2300 gcacaaggtc gacagagaaa accttcacca tcccagtgac tgatataaac   #            2350 agtgggatcc caggaattga tgaggtcatg aagactacca aaatcatcat   #            2400 tgggtgtttt gtggccatca cactcatggc tgcagtgatg ctggtcattt   #            2450 tctacaagat gaggaagcag caccatcggc aaaaccatca cgccccaaca   #            2500 aggactgttg aaattattaa tgtggatgat gagattacgg gagacacacc   #            2550 catggaaagc cacctgccca tgcctgctat cgagcatgag cacctaaatc   #            2600 actataactc atacaaatct cccttcaacc acacaacaac agttaacaca   #            2650 ataaattcaa tacacagttc agtgcatgaa ccgttattga tccgaatgaa   #            2700 ctctaaagac aatgtacaag agactcaaat ctaaaacatt tacagagtta   #            2750 caaaaaacaa acaatcaaaa aaaaagacag tttattaaaa atgacacaaa   #            2800 tgactgggct aaatctactg tttcaaaaaa gtgtctttac aaaaaaacaa   #            2850 aaaagaaaag aaatttattt attaaaaatt ctattgtgat ctaaagcaga   #            2900 caaaaa                  #                   #                   #         2906 <210> SEQ ID NO 292 <211> LENGTH: 640 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 292 Met Leu Asn Lys Met Thr Leu His Pro Gln Gl #n Ile Met Ile Gly   1               5  #                 10  #                 15 Pro Arg Phe Asn Arg Ala Leu Phe Asp Pro Le #u Leu Val Val Leu                  20  #                 25  #                 30 Leu Ala Leu Gln Leu Leu Val Val Ala Gly Le #u Val Arg Ala Gln                  35  #                 40  #                 45 Thr Cys Pro Ser Val Cys Ser Cys Ser Asn Gl #n Phe Ser Lys Val                  50  #                 55  #                 60 Ile Cys Val Arg Lys Asn Leu Arg Glu Val Pr #o Asp Gly Ile Ser                  65  #                 70  #                 75 Thr Asn Thr Arg Leu Leu Asn Leu His Glu As #n Gln Ile Gln Ile                  80  #                 85  #                 90 Ile Lys Val Asn Ser Phe Lys His Leu Arg Hi #s Leu Glu Ile Leu                  95  #                100  #                105 Gln Leu Ser Arg Asn His Ile Arg Thr Ile Gl #u Ile Gly Ala Phe                 110   #               115   #               120 Asn Gly Leu Ala Asn Leu Asn Thr Leu Glu Le #u Phe Asp Asn Arg                 125   #               130   #               135 Leu Thr Thr Ile Pro Asn Gly Ala Phe Val Ty #r Leu Ser Lys Leu                 140   #               145   #               150 Lys Glu Leu Trp Leu Arg Asn Asn Pro Ile Gl #u Ser Ile Pro Ser                 155   #               160   #               165 Tyr Ala Phe Asn Arg Ile Pro Ser Leu Arg Ar #g Leu Asp Leu Gly                 170   #               175   #               180 Glu Leu Lys Arg Leu Ser Tyr Ile Ser Glu Gl #y Ala Phe Glu Gly                 185   #               190   #               195 Leu Ser Asn Leu Arg Tyr Leu Asn Leu Ala Me #t Cys Asn Leu Arg                 200   #               205   #               210 Glu Ile Pro Asn Leu Thr Pro Leu Ile Lys Le #u Asp Glu Leu Asp                 215   #               220   #               225 Leu Ser Gly Asn His Leu Ser Ala Ile Arg Pr #o Gly Ser Phe Gln                 230   #               235   #               240 Gly Leu Met His Leu Gln Lys Leu Trp Met Il #e Gln Ser Gln Ile                 245   #               250   #               255 Gln Val Ile Glu Arg Asn Ala Phe Asp Asn Le #u Gln Ser Leu Val                 260   #               265   #               270 Glu Ile Asn Leu Ala His Asn Asn Leu Thr Le #u Leu Pro His Asp                 275   #               280   #               285 Leu Phe Thr Pro Leu His His Leu Glu Arg Il #e His Leu His His                 290   #               295   #               300 Asn Pro Trp Asn Cys Asn Cys Asp Ile Leu Tr #p Leu Ser Trp Trp                 305   #               310   #               315 Ile Lys Asp Met Ala Pro Ser Asn Thr Ala Cy #s Cys Ala Arg Cys                 320   #               325   #               330 Asn Thr Pro Pro Asn Leu Lys Gly Arg Tyr Il #e Gly Glu Leu Asp                 335   #               340   #               345 Gln Asn Tyr Phe Thr Cys Tyr Ala Pro Val Il #e Val Glu Pro Pro                 350   #               355   #               360 Ala Asp Leu Asn Val Thr Glu Gly Met Ala Al #a Glu Leu Lys Cys                 365   #               370   #               375 Arg Ala Ser Thr Ser Leu Thr Ser Val Ser Tr #p Ile Thr Pro Asn                 380   #               385   #               390 Gly Thr Val Met Thr His Gly Ala Tyr Lys Va #l Arg Ile Ala Val                 395   #               400   #               405 Leu Ser Asp Gly Thr Leu Asn Phe Thr Asn Va #l Thr Val Gln Asp                 410   #               415   #               420 Thr Gly Met Tyr Thr Cys Met Val Ser Asn Se #r Val Gly Asn Thr                 425   #               430   #               435 Thr Ala Ser Ala Thr Leu Asn Val Thr Ala Al #a Thr Thr Thr Pro                 440   #               445   #               450 Phe Ser Tyr Phe Ser Thr Val Thr Val Glu Th #r Met Glu Pro Ser                 455   #               460   #               465 Gln Asp Glu Ala Arg Thr Thr Asp Asn Asn Va #l Gly Pro Thr Pro                 470   #               475   #               480 Val Val Asp Trp Glu Thr Thr Asn Val Thr Th #r Ser Leu Thr Pro                 485   #               490   #               495 Gln Ser Thr Arg Ser Thr Glu Lys Thr Phe Th #r Ile Pro Val Thr                 500   #               505   #               510 Asp Ile Asn Ser Gly Ile Pro Gly Ile Asp Gl #u Val Met Lys Thr                 515   #               520   #               525 Thr Lys Ile Ile Ile Gly Cys Phe Val Ala Il #e Thr Leu Met Ala                 530   #               535   #               540 Ala Val Met Leu Val Ile Phe Tyr Lys Met Ar #g Lys Gln His His                 545   #               550   #               555 Arg Gln Asn His His Ala Pro Thr Arg Thr Va #l Glu Ile Ile Asn                 560   #               565   #               570 Val Asp Asp Glu Ile Thr Gly Asp Thr Pro Me #t Glu Ser His Leu                 575   #               580   #               585 Pro Met Pro Ala Ile Glu His Glu His Leu As #n His Tyr Asn Ser                 590   #               595   #               600 Tyr Lys Ser Pro Phe Asn His Thr Thr Thr Va #l Asn Thr Ile Asn                 605   #               610   #               615 Ser Ile His Ser Ser Val His Glu Pro Leu Le #u Ile Arg Met Asn                 620   #               625   #               630 Ser Lys Asp Asn Val Gln Glu Thr Gln Ile                 635   #               640 <210> SEQ ID NO 293 <211> LENGTH: 4053 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 293 agccgacgct gctcaagctg caactctgtt gcagttggca gttcttttcg   #              50 gtttccctcc tgctgtttgg gggcatgaaa gggcttcgcc gccgggagta   #             100 aaagaaggaa ttgaccgggc agcgcgaggg aggagcgcgc acgcgaccgc   #             150 gagggcgggc gtgcaccctc ggctggaagt ttgtgccggg ccccgagcgc   #             200 gcgccggctg ggagcttcgg gtagagacct aggccgctgg accgcgatga   #             250 gcgcgccgag cctccgtgcg cgcgccgcgg ggttggggct gctgctgtgc   #             300 gcggtgctgg ggcgcgctgg ccggtccgac agcggcggtc gcggggaact   #             350 cgggcagccc tctggggtag ccgccgagcg cccatgcccc actacctgcc   #             400 gctgcctcgg ggacctgctg gactgcagtc gtaagcggct agcgcgtctt   #             450 cccgagccac tcccgtcctg ggtcgctcgg ctggacttaa gtcacaacag   #             500 attatctttc atcaaggcaa gttccatgag ccaccttcaa agccttcgag   #             550 aagtgaaact gaacaacaat gaattggaga ccattccaaa tctgggacca   #             600 gtctcggcaa atattacact tctctccttg gctggaaaca ggattgttga   #             650 aatactccct gaacatctga aagagtttca gtcccttgaa actttggacc   #             700 ttagcagcaa caatatttca gagctccaaa ctgcatttcc agccctacag   #             750 ctcaaatatc tgtatctcaa cagcaaccga gtcacatcaa tggaacctgg   #             800 gtattttgac aatttggcca acacactcct tgtgttaaag ctgaacagga   #             850 accgaatctc agctatccca cccaagatgt ttaaactgcc ccaactgcaa   #             900 catctcgaat tgaaccgaaa caagattaaa aatgtagatg gactgacatt   #             950 ccaaggcctt ggtgctctga agtctctgaa aatgcaaaga aatggagtaa   #            1000 cgaaacttat ggatggagct ttttgggggc tgagcaacat ggaaattttg   #            1050 cagctggacc ataacaacct aacagagatt accaaaggct ggctttacgg   #            1100 cttgctgatg ctgcaggaac ttcatctcag ccaaaatgcc atcaacagga   #            1150 tcagccctga tgcctgggag ttctgccaga agctcagtga gctggaccta   #            1200 actttcaatc acttatcaag gttagatgat tcaagcttcc ttggcctaag   #            1250 cttactaaat acactgcaca ttgggaacaa cagagtcagc tacattgctg   #            1300 attgtgcctt ccgggggctt tccagtttaa agactttgga tctgaagaac   #            1350 aatgaaattt cctggactat tgaagacatg aatggtgctt tctctgggct   #            1400 tgacaaactg aggcgactga tactccaagg aaatcggatc cgttctatta   #            1450 ctaaaaaagc cttcactggt ttggatgcat tggagcatct agacctgagt   #            1500 gacaacgcaa tcatgtcttt acaaggcaat gcattttcac aaatgaagaa   #            1550 actgcaacaa ttgcatttaa atacatcaag ccttttgtgc gattgccagc   #            1600 taaaatggct cccacagtgg gtggcggaaa acaactttca gagctttgta   #            1650 aatgccagtt gtgcccatcc tcagctgcta aaaggaagaa gcatttttgc   #            1700 tgttagccca gatggctttg tgtgtgatga ttttcccaaa ccccagatca   #            1750 cggttcagcc agaaacacag tcggcaataa aaggttccaa tttgagtttc   #            1800 atctgctcag ctgccagcag cagtgattcc ccaatgactt ttgcttggaa   #            1850 aaaagacaat gaactactgc atgatgctga aatggaaaat tatgcacacc   #            1900 tccgggccca aggtggcgag gtgatggagt ataccaccat ccttcggctg   #            1950 cgcgaggtgg aatttgccag tgaggggaaa tatcagtgtg tcatctccaa   #            2000 tcactttggt tcatcctact ctgtcaaagc caagcttaca gtaaatatgc   #            2050 ttccctcatt caccaagacc cccatggatc tcaccatccg agctggggcc   #            2100 atggcacgct tggagtgtgc tgctgtgggg cacccagccc cccagatagc   #            2150 ctggcagaag gatgggggca cagacttccc agctgcacgg gagagacgca   #            2200 tgcatgtgat gcccgaggat gacgtgttct ttatcgtgga tgtgaagata   #            2250 gaggacattg gggtatacag ctgcacagct cagaacagtg caggaagtat   #            2300 ttcagcaaat gcaactctga ctgtcctaga aacaccatca tttttgcggc   #            2350 cactgttgga ccgaactgta accaagggag aaacagccgt cctacagtgc   #            2400 attgctggag gaagccctcc ccctaaactg aactggacca aagatgatag   #            2450 cccattggtg gtaaccgaga ggcacttttt tgcagcaggc aatcagcttc   #            2500 tgattattgt ggactcagat gtcagtgatg ctgggaaata cacatgtgag   #            2550 atgtctaaca cccttggcac tgagagagga aacgtgcgcc tcagtgtgat   #            2600 ccccactcca acctgcgact cccctcagat gacagcccca tcgttagacg   #            2650 atgacggatg ggccactgtg ggtgtcgtga tcatagccgt ggtttgctgt   #            2700 gtggtgggca cgtcactcgt gtgggtggtc atcatatacc acacaaggcg   #            2750 gaggaatgaa gattgcagca ttaccaacac agatgagacc aacttgccag   #            2800 cagatattcc tagttatttg tcatctcagg gaacgttagc tgacaggcag   #            2850 gatgggtacg tgtcttcaga aagtggaagc caccaccagt ttgtcacatc   #            2900 ttcaggtgct ggatttttct taccacaaca tgacagtagt gggacctgcc   #            2950 atattgacaa tagcagtgaa gctgatgtgg aagctgccac agatctgttc   #            3000 ctttgtccgt ttttgggatc cacaggccct atgtatttga agggaaatgt   #            3050 gtatggctca gatccttttg aaacatatca tacaggttgc agtcctgacc   #            3100 caagaacagt tttaatggac cactatgagc ccagttacat aaagaaaaag   #            3150 gagtgctacc catgttctca tccttcagaa gaatcctgcg aacggagctt   #            3200 cagtaatata tcgtggcctt cacatgtgag gaagctactt aacactagtt   #            3250 actctcacaa tgaaggacct ggaatgaaaa atctgtgtct aaacaagtcc   #            3300 tctttagatt ttagtgcaaa tccagagcca gcgtcggttg cctcgagtaa   #            3350 ttctttcatg ggtacctttg gaaaagctct caggagacct cacctagatg   #            3400 cctattcaag ctttggacag ccatcagatt gtcagccaag agccttttat   #            3450 ttgaaagctc attcttcccc agacttggac tctgggtcag aggaagatgg   #            3500 gaaagaaagg acagattttc aggaagaaaa tcacatttgt acctttaaac   #            3550 agactttaga aaactacagg actccaaatt ttcagtctta tgacttggac   #            3600 acatagactg aatgagacca aaggaaaagc ttaacatact acctcaagtg   #            3650 aacttttatt taaaagagag agaatcttat gttttttaaa tggagttatg   #            3700 aattttaaaa ggataaaaat gctttattta tacagatgaa ccaaaattac   #            3750 aaaaagttat gaaaattttt atactgggaa tgatgctcat ataagaatac   #            3800 ctttttaaac tattttttaa ctttgtttta tgcaaaaaag tatcttacgt   #            3850 aaattaatga tataaatcat gattatttta tgtattttta taatgccaga   #            3900 tttcttttta tggaaaatga gttactaaag cattttaaat aatacctgcc   #            3950 ttgtaccatt ttttaaatag aagttacttc attatatttt gcacattata   #            4000 tttaataaaa tgtgtcaatt tgaaaaaaaa aaaaaaaaaa aaaaaaaaaa   #            4050 aaa                   #                   #                   #           4053 <210> SEQ ID NO 294 <211> LENGTH: 1119 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 294 Met Ser Ala Pro Ser Leu Arg Ala Arg Ala Al #a Gly Leu Gly Leu   1               5  #                 10  #                 15 Leu Leu Cys Ala Val Leu Gly Arg Ala Gly Ar #g Ser Asp Ser Gly                  20  #                 25  #                 30 Gly Arg Gly Glu Leu Gly Gln Pro Ser Gly Va #l Ala Ala Glu Arg                  35  #                 40  #                 45 Pro Cys Pro Thr Thr Cys Arg Cys Leu Gly As #p Leu Leu Asp Cys                  50  #                 55  #                 60 Ser Arg Lys Arg Leu Ala Arg Leu Pro Glu Pr #o Leu Pro Ser Trp                  65  #                 70  #                 75 Val Ala Arg Leu Asp Leu Ser His Asn Arg Le #u Ser Phe Ile Lys                  80  #                 85  #                 90 Ala Ser Ser Met Ser His Leu Gln Ser Leu Ar #g Glu Val Lys Leu                  95  #                100  #                105 Asn Asn Asn Glu Leu Glu Thr Ile Pro Asn Le #u Gly Pro Val Ser                 110   #               115   #               120 Ala Asn Ile Thr Leu Leu Ser Leu Ala Gly As #n Arg Ile Val Glu                 125   #               130   #               135 Ile Leu Pro Glu His Leu Lys Glu Phe Gln Se #r Leu Glu Thr Leu                 140   #               145   #               150 Asp Leu Ser Ser Asn Asn Ile Ser Glu Leu Gl #n Thr Ala Phe Pro                 155   #               160   #               165 Ala Leu Gln Leu Lys Tyr Leu Tyr Leu Asn Se #r Asn Arg Val Thr                 170   #               175   #               180 Ser Met Glu Pro Gly Tyr Phe Asp Asn Leu Al #a Asn Thr Leu Leu                 185   #               190   #               195 Val Leu Lys Leu Asn Arg Asn Arg Ile Ser Al #a Ile Pro Pro Lys                 200   #               205   #               210 Met Phe Lys Leu Pro Gln Leu Gln His Leu Gl #u Leu Asn Arg Asn                 215   #               220   #               225 Lys Ile Lys Asn Val Asp Gly Leu Thr Phe Gl #n Gly Leu Gly Ala                 230   #               235   #               240 Leu Lys Ser Leu Lys Met Gln Arg Asn Gly Va #l Thr Lys Leu Met                 245   #               250   #               255 Asp Gly Ala Phe Trp Gly Leu Ser Asn Met Gl #u Ile Leu Gln Leu                 260   #               265   #               270 Asp His Asn Asn Leu Thr Glu Ile Thr Lys Gl #y Trp Leu Tyr Gly                 275   #               280   #               285 Leu Leu Met Leu Gln Glu Leu His Leu Ser Gl #n Asn Ala Ile Asn                 290   #               295   #               300 Arg Ile Ser Pro Asp Ala Trp Glu Phe Cys Gl #n Lys Leu Ser Glu                 305   #               310   #               315 Leu Asp Leu Thr Phe Asn His Leu Ser Arg Le #u Asp Asp Ser Ser                 320   #               325   #               330 Phe Leu Gly Leu Ser Leu Leu Asn Thr Leu Hi #s Ile Gly Asn Asn                 335   #               340   #               345 Arg Val Ser Tyr Ile Ala Asp Cys Ala Phe Ar #g Gly Leu Ser Ser                 350   #               355   #               360 Leu Lys Thr Leu Asp Leu Lys Asn Asn Glu Il #e Ser Trp Thr Ile                 365   #               370   #               375 Glu Asp Met Asn Gly Ala Phe Ser Gly Leu As #p Lys Leu Arg Arg                 380   #               385   #               390 Leu Ile Leu Gln Gly Asn Arg Ile Arg Ser Il #e Thr Lys Lys Ala                 395   #               400   #               405 Phe Thr Gly Leu Asp Ala Leu Glu His Leu As #p Leu Ser Asp Asn                 410   #               415   #               420 Ala Ile Met Ser Leu Gln Gly Asn Ala Phe Se #r Gln Met Lys Lys                 425   #               430   #               435 Leu Gln Gln Leu His Leu Asn Thr Ser Ser Le #u Leu Cys Asp Cys                 440   #               445   #               450 Gln Leu Lys Trp Leu Pro Gln Trp Val Ala Gl #u Asn Asn Phe Gln                 455   #               460   #               465 Ser Phe Val Asn Ala Ser Cys Ala His Pro Gl #n Leu Leu Lys Gly                 470   #               475   #               480 Arg Ser Ile Phe Ala Val Ser Pro Asp Gly Ph #e Val Cys Asp Asp                 485   #               490   #               495 Phe Pro Lys Pro Gln Ile Thr Val Gln Pro Gl #u Thr Gln Ser Ala                 500   #               505   #               510 Ile Lys Gly Ser Asn Leu Ser Phe Ile Cys Se #r Ala Ala Ser Ser                 515   #               520   #               525 Ser Asp Ser Pro Met Thr Phe Ala Trp Lys Ly #s Asp Asn Glu Leu                 530   #               535   #               540 Leu His Asp Ala Glu Met Glu Asn Tyr Ala Hi #s Leu Arg Ala Gln                 545   #               550   #               555 Gly Gly Glu Val Met Glu Tyr Thr Thr Ile Le #u Arg Leu Arg Glu                 560   #               565   #               570 Val Glu Phe Ala Ser Glu Gly Lys Tyr Gln Cy #s Val Ile Ser Asn                 575   #               580   #               585 His Phe Gly Ser Ser Tyr Ser Val Lys Ala Ly #s Leu Thr Val Asn                 590   #               595   #               600 Met Leu Pro Ser Phe Thr Lys Thr Pro Met As #p Leu Thr Ile Arg                 605   #               610   #               615 Ala Gly Ala Met Ala Arg Leu Glu Cys Ala Al #a Val Gly His Pro                 620   #               625   #               630 Ala Pro Gln Ile Ala Trp Gln Lys Asp Gly Gl #y Thr Asp Phe Pro                 635   #               640   #               645 Ala Ala Arg Glu Arg Arg Met His Val Met Pr #o Glu Asp Asp Val                 650   #               655   #               660 Phe Phe Ile Val Asp Val Lys Ile Glu Asp Il #e Gly Val Tyr Ser                 665   #               670   #               675 Cys Thr Ala Gln Asn Ser Ala Gly Ser Ile Se #r Ala Asn Ala Thr                 680   #               685   #               690 Leu Thr Val Leu Glu Thr Pro Ser Phe Leu Ar #g Pro Leu Leu Asp                 695   #               700   #               705 Arg Thr Val Thr Lys Gly Glu Thr Ala Val Le #u Gln Cys Ile Ala                 710   #               715   #               720 Gly Gly Ser Pro Pro Pro Lys Leu Asn Trp Th #r Lys Asp Asp Ser                 725   #               730   #               735 Pro Leu Val Val Thr Glu Arg His Phe Phe Al #a Ala Gly Asn Gln                 740   #               745   #               750 Leu Leu Ile Ile Val Asp Ser Asp Val Ser As #p Ala Gly Lys Tyr                 755   #               760   #               765 Thr Cys Glu Met Ser Asn Thr Leu Gly Thr Gl #u Arg Gly Asn Val                 770   #               775   #               780 Arg Leu Ser Val Ile Pro Thr Pro Thr Cys As #p Ser Pro Gln Met                 785   #               790   #               795 Thr Ala Pro Ser Leu Asp Asp Asp Gly Trp Al #a Thr Val Gly Val                 800   #               805   #               810 Val Ile Ile Ala Val Val Cys Cys Val Val Gl #y Thr Ser Leu Val                 815   #               820   #               825 Trp Val Val Ile Ile Tyr His Thr Arg Arg Ar #g Asn Glu Asp Cys                 830   #               835   #               840 Ser Ile Thr Asn Thr Asp Glu Thr Asn Leu Pr #o Ala Asp Ile Pro                 845   #               850   #               855 Ser Tyr Leu Ser Ser Gln Gly Thr Leu Ala As #p Arg Gln Asp Gly                 860   #               865   #               870 Tyr Val Ser Ser Glu Ser Gly Ser His His Gl #n Phe Val Thr Ser                 875   #               880   #               885 Ser Gly Ala Gly Phe Phe Leu Pro Gln His As #p Ser Ser Gly Thr                 890   #               895   #               900 Cys His Ile Asp Asn Ser Ser Glu Ala Asp Va #l Glu Ala Ala Thr                 905   #               910   #               915 Asp Leu Phe Leu Cys Pro Phe Leu Gly Ser Th #r Gly Pro Met Tyr                 920   #               925   #               930 Leu Lys Gly Asn Val Tyr Gly Ser Asp Pro Ph #e Glu Thr Tyr His                 935   #               940   #               945 Thr Gly Cys Ser Pro Asp Pro Arg Thr Val Le #u Met Asp His Tyr                 950   #               955   #               960 Glu Pro Ser Tyr Ile Lys Lys Lys Glu Cys Ty #r Pro Cys Ser His                 965   #               970   #               975 Pro Ser Glu Glu Ser Cys Glu Arg Ser Phe Se #r Asn Ile Ser Trp                 980   #               985   #               990 Pro Ser His Val Arg Lys Leu Leu Asn Thr Se #r Tyr Ser His Asn                 995   #              1000    #             1005 Glu Gly Pro Gly Met Lys Asn Leu Cys Leu As #n Lys Ser Ser Leu                1010   #              1015    #             1020 Asp Phe Ser Ala Asn Pro Glu Pro Ala Ser Va #l Ala Ser Ser Asn                1025   #              1030    #             1035 Ser Phe Met Gly Thr Phe Gly Lys Ala Leu Ar #g Arg Pro His Leu                1040   #              1045    #             1050 Asp Ala Tyr Ser Ser Phe Gly Gln Pro Ser As #p Cys Gln Pro Arg                1055   #              1060    #             1065 Ala Phe Tyr Leu Lys Ala His Ser Ser Pro As #p Leu Asp Ser Gly                1070   #              1075    #             1080 Ser Glu Glu Asp Gly Lys Glu Arg Thr Asp Ph #e Gln Glu Glu Asn                1085   #              1090    #             1095 His Ile Cys Thr Phe Lys Gln Thr Leu Glu As #n Tyr Arg Thr Pro                1100   #              1105    #             1110 Asn Phe Gln Ser Tyr Asp Leu Asp Thr                1115 <210> SEQ ID NO 295 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 295 ggaaccgaat ctcagcta              #                   #                   #  18 <210> SEQ ID NO 296 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 296 cctaaactga actggacca              #                   #                   # 19 <210> SEQ ID NO 297 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 297 ggctggagac actgaacct              #                   #                   # 19 <210> SEQ ID NO 298 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 298 acagctgcac agctcagaac agtg           #                   #                24 <210> SEQ ID NO 299 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 299 cattcccagt ataaaaattt tc            #                   #                 22 <210> SEQ ID NO 300 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 300 gggtcttggt gaatgagg              #                   #                   #  18 <210> SEQ ID NO 301 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 301 gtgcctctcg gttaccacca atgg           #                   #                24 <210> SEQ ID NO 302 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 302 gcggccactg ttggaccgaa ctgtaaccaa gggagaaaca gccgtcctac   #              50 <210> SEQ ID NO 303 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 303 gcctttgaca accttcagtc actagtgg          #                   #             28 <210> SEQ ID NO 304 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 304 ccccatgtgt ccatgactgt tccc           #                   #                24 <210> SEQ ID NO 305 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 305 tactgcctca tgacctcttc actcccttgc atcatcttag agcgg    #                   #45 <210> SEQ ID NO 306 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 306 actccaagga aatcggatcc gttc           #                   #                24 <210> SEQ ID NO 307 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 307 ttagcagctg aggatgggca caac           #                   #                24 <210> SEQ ID NO 308 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 308 actccaagga aatcggatcc gttc           #                   #                24 <210> SEQ ID NO 309 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 309 gccttcactg gtttggatgc attggagcat ctagacctga gtgacaacgc   #              50 <210> SEQ ID NO 310 <211> LENGTH: 3296 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 310 caaaacttgc gtcgcggaga gcgcccagct tgacttgaat ggaaggagcc   #              50 cgagcccgcg gagcgcagct gagactgggg gagcgcgttc ggcctgtggg   #             100 gcgccgctcg gcgccggggc gcagcaggga aggggaagct gtggtctgcc   #             150 ctgctccacg aggcgccact ggtgtgaacc gggagagccc ctgggtggtc   #             200 ccgtccccta tccctccttt atatagaaac cttccacact gggaaggcag   #             250 cggcgaggca ggagggctca tggtgagcaa ggaggccggc tgatctgcag   #             300 gcgcacagca ttccgagttt acagattttt acagatacca aatggaaggc   #             350 gaggaggcag aacagcctgc ctggttccat cagccctggc gcccaggcgc   #             400 atctgactcg gcaccccctg caggcaccat ggcccagagc cgggtgctgc   #             450 tgctcctgct gctgctgccg ccacagctgc acctgggacc tgtgcttgcc   #             500 gtgagggccc caggatttgg ccgaagtggc ggccacagcc tgagccccga   #             550 agagaacgaa tttgcggagg aggagccggt gctggtactg agccctgagg   #             600 agcccgggcc tggcccagcc gcggtcagct gcccccgaga ctgtgcctgt   #             650 tcccaggagg gcgtcgtgga ctgtggcggt attgacctgc gtgagttccc   #             700 gggggacctg cctgagcaca ccaaccacct atctctgcag aacaaccagc   #             750 tggaaaagat ctaccctgag gagctctccc ggctgcaccg gctggagaca   #             800 ctgaacctgc aaaacaaccg cctgacttcc cgagggctcc cagagaaggc   #             850 gtttgagcat ctgaccaacc tcaattacct gtacttggcc aataacaagc   #             900 tgaccttggc accccgcttc ctgccaaacg ccctgatcag tgtggacttt   #             950 gctgccaact atctcaccaa gatctatggg ctcacctttg gccagaagcc   #            1000 aaacttgagg tctgtgtacc tgcacaacaa caagctggca gacgccgggc   #            1050 tgccggacaa catgttcaac ggctccagca acgtcgaggt cctcatcctg   #            1100 tccagcaact tcctgcgcca cgtgcccaag cacctgccgc ctgccctgta   #            1150 caagctgcac ctcaagaaca acaagctgga gaagatcccc ccgggggcct   #            1200 tcagcgagct gagcagcctg cgcgagctat acctgcagaa caactacctg   #            1250 actgacgagg gcctggacaa cgagaccttc tggaagctct ccagcctgga   #            1300 gtacctggat ctgtccagca acaacctgtc tcgggtccca gctgggctgc   #            1350 cgcgcagcct ggtgctgctg cacttggaga agaacgccat ccggagcgtg   #            1400 gacgcgaatg tgctgacccc catccgcagc ctggagtacc tgctgctgca   #            1450 cagcaaccag ctgcgggagc agggcatcca cccactggcc ttccagggcc   #            1500 tcaagcggtt gcacacggtg cacctgtaca acaacgcgct ggagcgcgtg   #            1550 cccagtggcc tgcctcgccg cgtgcgcacc ctcatgatcc tgcacaacca   #            1600 gatcacaggc attggccgcg aagactttgc caccacctac ttcctggagg   #            1650 agctcaacct cagctacaac cgcatcacca gcccacaggt gcaccgcgac   #            1700 gccttccgca agctgcgcct gctgcgctcg ctggacctgt cgggcaaccg   #            1750 gctgcacacg ctgccacctg ggctgcctcg aaatgtccat gtgctgaagg   #            1800 tcaagcgcaa tgagctggct gccttggcac gaggggcgct ggcgggcatg   #            1850 gctcagctgc gtgagctgta cctcaccagc aaccgactgc gcagccgagc   #            1900 cctgggcccc cgtgcctggg tggacctcgc ccatctgcag ctgctggaca   #            1950 tcgccgggaa tcagctcaca gagatccccg aggggctccc cgagtcactt   #            2000 gagtacctgt acctgcagaa caacaagatt agtgcggtgc ccgccaatgc   #            2050 cttcgactcc acgcccaacc tcaaggggat ctttctcagg tttaacaagc   #            2100 tggctgtggg ctccgtggtg gacagtgcct tccggaggct gaagcacctg   #            2150 caggtcttgg acattgaagg caacttagag tttggtgaca tttccaagga   #            2200 ccgtggccgc ttggggaagg aaaaggagga ggaggaagag gaggaggagg   #            2250 aggaagagga aacaagatag tgacaaggtg atgcagatgt gacctaggat   #            2300 gatggaccgc cggactcttt tctgcagcac acgcctgtgt gctgtgagcc   #            2350 ccccactctg ccgtgctcac acagacacac ccagctgcac acatgaggca   #            2400 tcccacatga cacgggctga cacagtctca tatccccacc ccttcccacg   #            2450 gcgtgtccca cggccagaca catgcacaca catcacaccc tcaaacaccc   #            2500 agctcagcca cacacaacta ccctccaaac caccacagtc tctgtcacac   #            2550 ccccactacc gctgccacgc cctctgaatc atgcagggaa gggtctgccc   #            2600 ctgccctggc acacacaggc acccattccc tccccctgct gacatgtgta   #            2650 tgcgtatgca tacacaccac acacacacac atgcacaagt catgtgcgaa   #            2700 cagccctcca aagcctatgc cacagacagc tcttgcccca gccagaatca   #            2750 gccatagcag ctcgccgtct gccctgtcca tctgtccgtc cgttccctgg   #            2800 agaagacaca agggtatcca tgctctgtgg ccaggtgcct gccaccctct   #            2850 ggaactcaca aaagctggct tttattcctt tcccatccta tggggacagg   #            2900 agccttcagg actgctggcc tggcctggcc caccctgctc ctccaggtgc   #            2950 tgggcagtca ctctgctaag agtccctccc tgccacgccc tggcaggaca   #            3000 caggcacttt tccaatgggc aagcccagtg gaggcaggat gggagagccc   #            3050 cctgggtgct gctggggcct tggggcagga gtgaagcaga ggtgatgggg   #            3100 ctgggctgag ccagggagga aggacccagc tgcacctagg agacaccttt   #            3150 gttcttcagg cctgtggggg aagttccggg tgcctttatt ttttattctt   #            3200 ttctaaggaa aaaaatgata aaaatctcaa agctgatttt tcttgttata   #            3250 gaaaaactaa tataaaagca ttatccctat ccctgcaaaa aaaaaa    #               3296 <210> SEQ ID NO 311 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 311 gcattggccg cgagactttg cc            #                   #                 22 <210> SEQ ID NO 312 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 312 gcggccacgg tccttggaaa tg            #                   #                 22 <210> SEQ ID NO 313 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 313 tggaggagct caacctcagc tacaaccgca tcaccagccc acagg    #                   #45 <210> SEQ ID NO 314 <211> LENGTH: 3003 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 314 gggagggggc tccgggcgcc gcgcagcaga cctgctccgg ccgcgcgcct   #              50 cgccgctgtc ctccgggagc ggcagcagta gcccgggcgg cgagggctgg   #             100 gggttcctcg agactctcag aggggcgcct cccatcggcg cccaccaccc   #             150 caacctgttc ctcgcgcgcc actgcgctgc gccccaggac ccgctgccca   #             200 acatggattt tctcctggcg ctggtgctgg tatcctcgct ctacctgcag   #             250 gcggccgccg agttcgacgg gaggtggccc aggcaaatag tgtcatcgat   #             300 tggcctatgt cgttatggtg ggaggattga ctgctgctgg ggctgggctc   #             350 gccagtcttg gggacagtgt cagcctgtgt gccaaccacg atgcaaacat   #             400 ggtgaatgta tcgggccaaa caagtgcaag tgtcatcctg gttatgctgg   #             450 aaaaacctgt aatcaagatc taaatgagtg tggcctgaag ccccggccct   #             500 gtaagcacag gtgcatgaac acttacggca gctacaagtg ctactgtctc   #             550 aacggatata tgctcatgcc ggatggttcc tgctcaagtg ccctgacctg   #             600 ctccatggca aactgtcagt atggctgtga tgttgttaaa ggacaaatac   #             650 ggtgccagtg cccatcccct ggcctgcacc tggctcctga tgggaggacc   #             700 tgtgtagatg ttgatgaatg tgctacagga agagcctcct gccctagatt   #             750 taggcaatgt gtcaacactt ttgggagcta catctgcaag tgtcataaag   #             800 gcttcgatct catgtatatt ggaggcaaat atcaatgtca tgacatagac   #             850 gaatgctcac ttggtcagta tcagtgcagc agctttgctc gatgttataa   #             900 cgtacgtggg tcctacaagt gcaaatgtaa agaaggatac cagggtgatg   #             950 gactgacttg tgtgtatatc ccaaaagtta tgattgaacc ttcaggtcca   #            1000 attcatgtac caaagggaaa tggtaccatt ttaaagggtg acacaggaaa   #            1050 taataattgg attcctgatg ttggaagtac ttggtggcct ccgaagacac   #            1100 catatattcc tcctatcatt accaacaggc ctacttctaa gccaacaaca   #            1150 agacctacac caaagccaac accaattcct actccaccac caccaccacc   #            1200 cctgccaaca gagctcagaa cacctctacc acctacaacc ccagaaaggc   #            1250 caaccaccgg actgacaact atagcaccag ctgccagtac acctccagga   #            1300 gggattacag ttgacaacag ggtacagaca gaccctcaga aacccagagg   #            1350 agatgtgttc agtgttctgg tacacagttg taattttgac catggacttt   #            1400 gtggatggat cagggagaaa gacaatgact tgcactggga accaatcagg   #            1450 gacccagcag gtggacaata tctgacagtg tcggcagcca aagccccagg   #            1500 gggaaaagct gcacgcttgg tgctacctct cggccgcctc atgcattcag   #            1550 gggacctgtg cctgtcattc aggcacaagg tgacggggct gcactctggc   #            1600 acactccagg tgtttgtgag aaaacacggt gcccacggag cagccctgtg   #            1650 gggaagaaat ggtggccatg gctggaggca aacacagatc accttgcgag   #            1700 gggctgacat caagagcgaa tcacaaagat gattaaaggg ttggaaaaaa   #            1750 agatctatga tggaaaatta aaggaactgg gattattgag cctggagaag   #            1800 agaagactga ggggcaaacc attgatggtt ttcaagtata tgaagggttg   #            1850 gcacagagag ggtggcgacc agctgttctc catatgcact aagaatagaa   #            1900 caagaggaaa ctggcttaga ctagagtata agggagcatt tcttggcagg   #            1950 ggccattgtt agaatacttc ataaaaaaag aagtgtgaaa atctcagtat   #            2000 ctctctctct ttctaaaaaa ttagataaaa atttgtctat ttaagatggt   #            2050 taaagatgtt cttacccaag gaaaagtaac aaattataga atttcccaaa   #            2100 agatgttttg atcctactag tagtatgcag tgaaaatctt tagaactaaa   #            2150 taatttggac aaggcttaat ttaggcattt ccctcttgac ctcctaatgg   #            2200 agagggattg aaaggggaag agcccaccaa atgctgagct cactgaaata   #            2250 tctctccctt atggcaatcc tagcagtatt aaagaaaaaa ggaaactatt   #            2300 tattccaaat gagagtatga tggacagata ttttagtatc tcagtaatgt   #            2350 cctagtgtgg cggtggtttt caatgtttct tcatggtaaa ggtataagcc   #            2400 tttcatttgt tcaatggatg atgtttcaga tttttttttt tttaagagat   #            2450 ccttcaagga acacagttca gagagatttt catcgggtgc attctctctg   #            2500 cttcgtgtgt gacaagttat cttggctgct gagaaagagt gccctgcccc   #            2550 acaccggcag acctttcctt cacctcatca gtatgattca gtttctctta   #            2600 tcaattggac tctcccaggt tccacagaac agtaatattt tttgaacaat   #            2650 aggtacaata gaaggtcttc tgtcatttaa cctggtaaag gcagggctgg   #            2700 agggggaaaa taaatcatta agcctttgag taacggcaga atatatggct   #            2750 gtagatccat ttttaatggt tcatttcctt tatggtcata taactgcaca   #            2800 gctgaagatg aaaggggaaa ataaatgaaa attttacttt tcgatgccaa   #            2850 tgatacattg cactaaactg atggaagaag ttatccaaag tactgtataa   #            2900 catcttgttt attatttaat gttttctaaa ataaaaaatg ttagtggttt   #            2950 tccaaatggc ctaataaaaa caattatttg taaataaaaa cactgttagt   #            3000 aat                   #                   #                   #           3003 <210> SEQ ID NO 315 <211> LENGTH: 509 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 315 Met Asp Phe Leu Leu Ala Leu Val Leu Val Se #r Ser Leu Tyr Leu   1               5  #                 10  #                 15 Gln Ala Ala Ala Glu Phe Asp Gly Arg Trp Pr #o Arg Gln Ile Val                  20  #                 25  #                 30 Ser Ser Ile Gly Leu Cys Arg Tyr Gly Gly Ar #g Ile Asp Cys Cys                  35  #                 40  #                 45 Trp Gly Trp Ala Arg Gln Ser Trp Gly Gln Cy #s Gln Pro Val Cys                  50  #                 55  #                 60 Gln Pro Arg Cys Lys His Gly Glu Cys Ile Gl #y Pro Asn Lys Cys                  65  #                 70  #                 75 Lys Cys His Pro Gly Tyr Ala Gly Lys Thr Cy #s Asn Gln Asp Leu                  80  #                 85  #                 90 Asn Glu Cys Gly Leu Lys Pro Arg Pro Cys Ly #s His Arg Cys Met                  95  #                100  #                105 Asn Thr Tyr Gly Ser Tyr Lys Cys Tyr Cys Le #u Asn Gly Tyr Met                 110   #               115   #               120 Leu Met Pro Asp Gly Ser Cys Ser Ser Ala Le #u Thr Cys Ser Met                 125   #               130   #               135 Ala Asn Cys Gln Tyr Gly Cys Asp Val Val Ly #s Gly Gln Ile Arg                 140   #               145   #               150 Cys Gln Cys Pro Ser Pro Gly Leu His Leu Al #a Pro Asp Gly Arg                 155   #               160   #               165 Thr Cys Val Asp Val Asp Glu Cys Ala Thr Gl #y Arg Ala Ser Cys                 170   #               175   #               180 Pro Arg Phe Arg Gln Cys Val Asn Thr Phe Gl #y Ser Tyr Ile Cys                 185   #               190   #               195 Lys Cys His Lys Gly Phe Asp Leu Met Tyr Il #e Gly Gly Lys Tyr                 200   #               205   #               210 Gln Cys His Asp Ile Asp Glu Cys Ser Leu Gl #y Gln Tyr Gln Cys                 215   #               220   #               225 Ser Ser Phe Ala Arg Cys Tyr Asn Val Arg Gl #y Ser Tyr Lys Cys                 230   #               235   #               240 Lys Cys Lys Glu Gly Tyr Gln Gly Asp Gly Le #u Thr Cys Val Tyr                 245   #               250   #               255 Ile Pro Lys Val Met Ile Glu Pro Ser Gly Pr #o Ile His Val Pro                 260   #               265   #               270 Lys Gly Asn Gly Thr Ile Leu Lys Gly Asp Th #r Gly Asn Asn Asn                 275   #               280   #               285 Trp Ile Pro Asp Val Gly Ser Thr Trp Trp Pr #o Pro Lys Thr Pro                 290   #               295   #               300 Tyr Ile Pro Pro Ile Ile Thr Asn Arg Pro Th #r Ser Lys Pro Thr                 305   #               310   #               315 Thr Arg Pro Thr Pro Lys Pro Thr Pro Ile Pr #o Thr Pro Pro Pro                 320   #               325   #               330 Pro Pro Pro Leu Pro Thr Glu Leu Arg Thr Pr #o Leu Pro Pro Thr                 335   #               340   #               345 Thr Pro Glu Arg Pro Thr Thr Gly Leu Thr Th #r Ile Ala Pro Ala                 350   #               355   #               360 Ala Ser Thr Pro Pro Gly Gly Ile Thr Val As #p Asn Arg Val Gln                 365   #               370   #               375 Thr Asp Pro Gln Lys Pro Arg Gly Asp Val Ph #e Ser Val Leu Val                 380   #               385   #               390 His Ser Cys Asn Phe Asp His Gly Leu Cys Gl #y Trp Ile Arg Glu                 395   #               400   #               405 Lys Asp Asn Asp Leu His Trp Glu Pro Ile Ar #g Asp Pro Ala Gly                 410   #               415   #               420 Gly Gln Tyr Leu Thr Val Ser Ala Ala Lys Al #a Pro Gly Gly Lys                 425   #               430   #               435 Ala Ala Arg Leu Val Leu Pro Leu Gly Arg Le #u Met His Ser Gly                 440   #               445   #               450 Asp Leu Cys Leu Ser Phe Arg His Lys Val Th #r Gly Leu His Ser                 455   #               460   #               465 Gly Thr Leu Gln Val Phe Val Arg Lys His Gl #y Ala His Gly Ala                 470   #               475   #               480 Ala Leu Trp Gly Arg Asn Gly Gly His Gly Tr #p Arg Gln Thr Gln                 485   #               490   #               495 Ile Thr Leu Arg Gly Ala Asp Ile Lys Ser Gl #u Ser Gln Arg                 500   #               505 <210> SEQ ID NO 316 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 316 gatggttcct gctcaagtgc cctg           #                   #                24 <210> SEQ ID NO 317 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 317 ttgcacttgt aggacccacg tacg           #                   #                24 <210> SEQ ID NO 318 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 318 ctgatgggag gacctgtgta gatgttgatg aatgtgctac aggaagagcc   #              50 <210> SEQ ID NO 319 <211> LENGTH: 2110 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 319 cttctttgaa aaggattatc acctgatcag gttctctctg catttgcccc   #              50 tttagattgt gaaatgtggc tcaaggtctt cacaactttc ctttcctttg   #             100 caacaggtgc ttgctcgggg ctgaaggtga cagtgccatc acacactgtc   #             150 catggcgtca gaggtcaggc cctctaccta cccgtccact atggcttcca   #             200 cactccagca tcagacatcc agatcatatg gctatttgag agaccccaca   #             250 caatgcccaa atacttactg ggctctgtga ataagtctgt ggttcctgac   #             300 ttggaatacc aacacaagtt caccatgatg ccacccaatg catctctgct   #             350 tatcaaccca ctgcagttcc ctgatgaagg caattacatc gtgaaggtca   #             400 acattcaggg aaatggaact ctatctgcca gtcagaagat acaagtcacg   #             450 gttgatgatc ctgtcacaaa gccagtggtg cagattcatc ctccctctgg   #             500 ggctgtggag tatgtgggga acatgaccct gacatgccat gtggaagggg   #             550 gcactcggct agcttaccaa tggctaaaaa atgggagacc tgtccacacc   #             600 agctccacct actccttttc tccccaaaac aatacccttc atattgctcc   #             650 agtaaccaag gaagacattg ggaattacag ctgcctggtg aggaaccctg   #             700 tcagtgaaat ggaaagtgat atcattatgc ccatcatata ttatggacct   #             750 tatggacttc aagtgaattc tgataaaggg ctaaaagtag gggaagtgtt   #             800 tactgttgac cttggagagg ccatcctatt tgattgttct gctgattctc   #             850 atccccccaa cacctactcc tggattagga ggactgacaa tactacatat   #             900 atcattaagc atgggcctcg cttagaagtt gcatctgaga aagtagccca   #             950 gaagacaatg gactatgtgt gctgtgctta caacaacata accggcaggc   #            1000 aagatgaaac tcatttcaca gttatcatca cttccgtagg actggagaag   #            1050 cttgcacaga aaggaaaatc attgtcacct ttagcaagta taactggaat   #            1100 atcactattt ttgattatat ccatgtgtct tctcttccta tggaaaaaat   #            1150 atcaacccta caaagttata aaacagaaac tagaaggcag gccagaaaca   #            1200 gaatacagga aagctcaaac attttcaggc catgaagatg ctctggatga   #            1250 cttcggaata tatgaatttg ttgcttttcc agatgtttct ggtgtttcca   #            1300 ggattccaag caggtctgtt ccagcctctg attgtgtatc ggggcaagat   #            1350 ttgcacagta cagtgtatga agttattcag cacatccctg cccagcagca   #            1400 agaccatcca gagtgaactt tcatgggcta aacagtacat tcgagtgaaa   #            1450 ttctgaagaa acattttaag gaaaaacagt ggaaaagtat attaatctgg   #            1500 aatcagtgaa gaaaccagga ccaacacctc ttactcatta ttcctttaca   #            1550 tgcagaatag aggcatttat gcaaattgaa ctgcaggttt ttcagcatat   #            1600 acacaatgtc ttgtgcaaca gaaaaacatg ttggggaaat attcctcagt   #            1650 ggagagtcgt tctcatgctg acggggagaa cgaaagtgac aggggtttcc   #            1700 tcataagttt tgtatgaaat atctctacaa acctcaatta gttctactct   #            1750 acactttcac tatcatcaac actgagacta tcctgtctca cctacaaatg   #            1800 tggaaacttt acattgttcg atttttcagc agactttgtt ttattaaatt   #            1850 tttattagtg ttaagaatgc taaatttatg tttcaatttt atttccaaat   #            1900 ttctatcttg ttatttgtac aacaaagtaa taaggatggt tgtcacaaaa   #            1950 acaaaactat gccttctctt ttttttcaat caccagtagt atttttgaga   #            2000 agacttgtga acacttaagg aaatgactat taaagtctta tttttatttt   #            2050 tttcaaggaa agatggattc aaataaatta ttctgttttt gcttttaaaa   #            2100 aaaaaaaaaa                 #                   #                   #      2110 <210> SEQ ID NO 320 <211> LENGTH: 450 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 320 Met Trp Leu Lys Val Phe Thr Thr Phe Leu Se #r Phe Ala Thr Gly   1               5  #                 10  #                 15 Ala Cys Ser Gly Leu Lys Val Thr Val Pro Se #r His Thr Val His                  20  #                 25  #                 30 Gly Val Arg Gly Gln Ala Leu Tyr Leu Pro Va #l His Tyr Gly Phe                  35  #                 40  #                 45 His Thr Pro Ala Ser Asp Ile Gln Ile Ile Tr #p Leu Phe Glu Arg                  50  #                 55  #                 60 Pro His Thr Met Pro Lys Tyr Leu Leu Gly Se #r Val Asn Lys Ser                  65  #                 70  #                 75 Val Val Pro Asp Leu Glu Tyr Gln His Lys Ph #e Thr Met Met Pro                  80  #                 85  #                 90 Pro Asn Ala Ser Leu Leu Ile Asn Pro Leu Gl #n Phe Pro Asp Glu                  95  #                100  #                105 Gly Asn Tyr Ile Val Lys Val Asn Ile Gln Gl #y Asn Gly Thr Leu                 110   #               115   #               120 Ser Ala Ser Gln Lys Ile Gln Val Thr Val As #p Asp Pro Val Thr                 125   #               130   #               135 Lys Pro Val Val Gln Ile His Pro Pro Ser Gl #y Ala Val Glu Tyr                 140   #               145   #               150 Val Gly Asn Met Thr Leu Thr Cys His Val Gl #u Gly Gly Thr Arg                 155   #               160   #               165 Leu Ala Tyr Gln Trp Leu Lys Asn Gly Arg Pr #o Val His Thr Ser                 170   #               175   #               180 Ser Thr Tyr Ser Phe Ser Pro Gln Asn Asn Th #r Leu His Ile Ala                 185   #               190   #               195 Pro Val Thr Lys Glu Asp Ile Gly Asn Tyr Se #r Cys Leu Val Arg                 200   #               205   #               210 Asn Pro Val Ser Glu Met Glu Ser Asp Ile Il #e Met Pro Ile Ile                 215   #               220   #               225 Tyr Tyr Gly Pro Tyr Gly Leu Gln Val Asn Se #r Asp Lys Gly Leu                 230   #               235   #               240 Lys Val Gly Glu Val Phe Thr Val Asp Leu Gl #y Glu Ala Ile Leu                 245   #               250   #               255 Phe Asp Cys Ser Ala Asp Ser His Pro Pro As #n Thr Tyr Ser Trp                 260   #               265   #               270 Ile Arg Arg Thr Asp Asn Thr Thr Tyr Ile Il #e Lys His Gly Pro                 275   #               280   #               285 Arg Leu Glu Val Ala Ser Glu Lys Val Ala Gl #n Lys Thr Met Asp                 290   #               295   #               300 Tyr Val Cys Cys Ala Tyr Asn Asn Ile Thr Gl #y Arg Gln Asp Glu                 305   #               310   #               315 Thr His Phe Thr Val Ile Ile Thr Ser Val Gl #y Leu Glu Lys Leu                 320   #               325   #               330 Ala Gln Lys Gly Lys Ser Leu Ser Pro Leu Al #a Ser Ile Thr Gly                 335   #               340   #               345 Ile Ser Leu Phe Leu Ile Ile Ser Met Cys Le #u Leu Phe Leu Trp                 350   #               355   #               360 Lys Lys Tyr Gln Pro Tyr Lys Val Ile Lys Gl #n Lys Leu Glu Gly                 365   #               370   #               375 Arg Pro Glu Thr Glu Tyr Arg Lys Ala Gln Th #r Phe Ser Gly His                 380   #               385   #               390 Glu Asp Ala Leu Asp Asp Phe Gly Ile Tyr Gl #u Phe Val Ala Phe                 395   #               400   #               405 Pro Asp Val Ser Gly Val Ser Arg Ile Pro Se #r Arg Ser Val Pro                 410   #               415   #               420 Ala Ser Asp Cys Val Ser Gly Gln Asp Leu Hi #s Ser Thr Val Tyr                 425   #               430   #               435 Glu Val Ile Gln His Ile Pro Ala Gln Gln Gl #n Asp His Pro Glu                 440   #               445   #               450 <210> SEQ ID NO 321 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 321 gatcctgtca caaagccagt ggtgc           #                   #               25 <210> SEQ ID NO 322 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 322 cactgacagg gttcctcacc cagg           #                   #               24 <210> SEQ ID NO 323 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 323 ctccctctgg gctgtggagt atgtggggaa catgaccctg acatg    #                   #45 <210> SEQ ID NO 324 <211> LENGTH: 2397 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 324 gcaagcggcg aaatggcgcc ctccgggagt cttgcagttc ccctggcagt   #              50 cctggtgctg ttgctttggg gtgctccctg gacgcacggg cggcggagca   #             100 acgttcgcgt catcacggac gagaactgga gagaactgct ggaaggagac   #             150 tggatgatag aattttatgc cccgtggtgc cctgcttgtc aaaatcttca   #             200 accggaatgg gaaagttttg ctgaatgggg agaagatctt gaggttaata   #             250 ttgcgaaagt agatgtcaca gagcagccag gactgagtgg acggtttatc   #             300 ataactgctc ttcctactat ttatcattgt aaagatggtg aatttaggcg   #             350 ctatcagggt ccaaggacta agaaggactt cataaacttt ataagtgata   #             400 aagagtggaa gagtattgag cccgtttcat catggtttgg tccaggttct   #             450 gttctgatga gtagtatgtc agcactcttt cagctatcta tgtggatcag   #             500 gacgtgccat aactacttta ttgaagacct tggattgcca gtgtggggat   #             550 catatactgt ttttgcttta gcaactctgt tttccggact gttattagga   #             600 ctctgtatga tatttgtggc agattgcctt tgtccttcaa aaaggcgcag   #             650 accacagcca tacccatacc cttcaaaaaa attattatca gaatctgcac   #             700 aacctttgaa aaaagtggag gaggaacaag aggcggatga agaagatgtt   #             750 tcagaagaag aagctgaaag taaagaagga acaaacaaag actttccaca   #             800 gaatgccata agacaacgct ctctgggtcc atcattggcc acagataaat   #             850 cctagttaaa ttttatagtt atcttaatat tatgattttg ataaaaacag   #             900 aagattgatc attttgtttg gtttgaagtg aactgtgact tttttgaata   #             950 ttgcagggtt cagtctagat tgtcattaaa ttgaagagtc tacattcaga   #            1000 acataaaagc actaggtata caagtttgaa atatgattta agcacagtat   #            1050 gatggtttaa atagttctct aatttttgaa aaatcgtgcc aagcaataag   #            1100 atttatgtat atttgtttaa taataaccta tttcaagtct gagttttgaa   #            1150 aatttacatt tcccaagtat tgcattattg aggtatttaa gaagattatt   #            1200 ttagagaaaa atatttctca tttgatataa tttttctctg tttcactgtg   #            1250 tgaaaaaaag aagatatttc ccataaatgg gaagtttgcc cattgtctca   #            1300 agaaatgtgt atttcagtga caatttcgtg gtctttttag aggtatattc   #            1350 caaaatttcc ttgtattttt aggttatgca actaataaaa actaccttac   #            1400 attaattaat tacagttttc tacacatggt aatacaggat atgctactga   #            1450 tttaggaagt ttttaagttc atggtattct cttgattcca acaaagtttg   #            1500 attttctctt gtatttttct tacttactat gggttacatt ttttattttt   #            1550 caaattggat gataatttct tggaaacatt ttttatgttt tagtaaacag   #            1600 tatttttttg ttgtttcaaa ctgaagttta ctgagagatc catcaaattg   #            1650 aacaatctgt tgtaatttaa aattttggcc acttttttca gattttacat   #            1700 cattcttgct gaacttcaac ttgaaattgt tttttttttc tttttggatg   #            1750 tgaaggtgaa cattcctgat ttttgtctga tgtgaaaaag ccttggtatt   #            1800 ttacattttg aaaattcaaa gaagcttaat ataaaagttt gcattctact   #            1850 caggaaaaag catcttcttg tatatgtctt aaatgtattt ttgtcctcat   #            1900 atacagaaag ttcttaattg attttacagt ctgtaatgct tgatgtttta   #            1950 aaataataac atttttatat tttttaaaag acaaacttca tattatcctg   #            2000 tgttctttcc tgactggtaa tattgtgtgg gatttcacag gtaaaagtca   #            2050 gtaggatgga acattttagt gtatttttac tccttaaaga gctagaatac   #            2100 atagttttca ccttaaaaga agggggaaaa tcataaatac aatgaatcaa   #            2150 ctgaccatta cgtagtagac aatttctgta atgtcccctt ctttctaggc   #            2200 tctgttgctg tgtgaatcca ttagatttac agtatcgtaa tatacaagtt   #            2250 ttctttaaag ccctctcctt tagaatttaa aatattgtac cattaaagag   #            2300 tttggatgtg taacttgtga tgccttagaa aaatatccta agcacaaaat   #            2350 aaacctttct aaccacttca ttaaagctga aaaaaaaaaa aaaaaaa    #              2397 <210> SEQ ID NO 325 <211> LENGTH: 280 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 325 Met Ala Pro Ser Gly Ser Leu Ala Val Pro Le #u Ala Val Leu Val   1               5  #                 10  #                 15 Leu Leu Leu Trp Gly Ala Pro Trp Thr His Gl #y Arg Arg Ser Asn                  20  #                 25  #                 30 Val Arg Val Ile Thr Asp Glu Asn Trp Arg Gl #u Leu Leu Glu Gly                  35  #                 40  #                 45 Asp Trp Met Ile Glu Phe Tyr Ala Pro Trp Cy #s Pro Ala Cys Gln                  50  #                 55  #                 60 Asn Leu Gln Pro Glu Trp Glu Ser Phe Ala Gl #u Trp Gly Glu Asp                  65  #                 70  #                 75 Leu Glu Val Asn Ile Ala Lys Val Asp Val Th #r Glu Gln Pro Gly                  80  #                 85  #                 90 Leu Ser Gly Arg Phe Ile Ile Thr Ala Leu Pr #o Thr Ile Tyr His                  95  #                100  #                105 Cys Lys Asp Gly Glu Phe Arg Arg Tyr Gln Gl #y Pro Arg Thr Lys                 110   #               115   #               120 Lys Asp Phe Ile Asn Phe Ile Ser Asp Lys Gl #u Trp Lys Ser Ile                 125   #               130   #               135 Glu Pro Val Ser Ser Trp Phe Gly Pro Gly Se #r Val Leu Met Ser                 140   #               145   #               150 Ser Met Ser Ala Leu Phe Gln Leu Ser Met Tr #p Ile Arg Thr Cys                 155   #               160   #               165 His Asn Tyr Phe Ile Glu Asp Leu Gly Leu Pr #o Val Trp Gly Ser                 170   #               175   #               180 Tyr Thr Val Phe Ala Leu Ala Thr Leu Phe Se #r Gly Leu Leu Leu                 185   #               190   #               195 Gly Leu Cys Met Ile Phe Val Ala Asp Cys Le #u Cys Pro Ser Lys                 200   #               205   #               210 Arg Arg Arg Pro Gln Pro Tyr Pro Tyr Pro Se #r Lys Lys Leu Leu                 215   #               220   #               225 Ser Glu Ser Ala Gln Pro Leu Lys Lys Val Gl #u Glu Glu Gln Glu                 230   #               235   #               240 Ala Asp Glu Glu Asp Val Ser Glu Glu Glu Al #a Glu Ser Lys Glu                 245   #               250   #               255 Gly Thr Asn Lys Asp Phe Pro Gln Asn Ala Il #e Arg Gln Arg Ser                 260   #               265   #               270 Leu Gly Pro Ser Leu Ala Thr Asp Lys Ser                 275   #               280 <210> SEQ ID NO 326 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 326 tgaggtgggc aagcggcgaa atg            #                   #                23 <210> SEQ ID NO 327 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 327 tatgtggatc aggacgtgcc             #                   #                   # 20 <210> SEQ ID NO 328 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 328 tgcagggttc agtctagatt g            #                   #                   #21 <210> SEQ ID NO 329 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 329 ttgaaggaca aaggcaatct gccac           #                   #               25 <210> SEQ ID NO 330 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 330 ggagtcttgc agttcccctg gcagtcctgg tgctgttgct ttggg    #                   #45 <210> SEQ ID NO 331 <211> LENGTH: 2168 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 331 gcgagtgtcc agctgcggag acccgtgata attcgttaac taattcaaca   #              50 aacgggaccc ttctgtgtgc cagaaaccgc aagcagttgc taacccagtg   #             100 ggacaggcgg attggaagag cgggaaggtc ctggcccaga gcagtgtgac   #             150 acttccctct gtgaccatga aactctgggt gtctgcattg ctgatggcct   #             200 ggtttggtgt cctgagctgt gtgcaggccg aattcttcac ctctattggg   #             250 cacatgactg acctgattta tgcagagaaa gagctggtgc agtctctgaa   #             300 agagtacatc cttgtggagg aagccaagct ttccaagatt aagagctggg   #             350 ccaacaaaat ggaagccttg actagcaagt cagctgctga tgctgagggc   #             400 tacctggctc accctgtgaa tgcctacaaa ctggtgaagc ggctaaacac   #             450 agactggcct gcgctggagg accttgtcct gcaggactca gctgcaggtt   #             500 ttatcgccaa cctctctgtg cagcggcagt tcttccccac tgatgaggac   #             550 gagataggag ctgccaaagc cctgatgaga cttcaggaca catacaggct   #             600 ggacccaggc acaatttcca gaggggaact tccaggaacc aagtaccagg   #             650 caatgctgag tgtggatgac tgctttggga tgggccgctc ggcctacaat   #             700 gaaggggact attatcatac ggtgttgtgg atggagcagg tgctaaagca   #             750 gcttgatgcc ggggaggagg ccaccacaac caagtcacag gtgctggact   #             800 acctcagcta tgctgtcttc cagttgggtg atctgcaccg tgccctggag   #             850 ctcacccgcc gcctgctctc ccttgaccca agccacgaac gagctggagg   #             900 gaatctgcgg tactttgagc agttattgga ggaagagaga gaaaaaacgt   #             950 taacaaatca gacagaagct gagctagcaa ccccagaagg catctatgag   #            1000 aggcctgtgg actacctgcc tgagagggat gtttacgaga gcctctgtcg   #            1050 tggggagggt gtcaaactga caccccgtag acagaagagg cttttctgta   #            1100 ggtaccacca tggcaacagg gccccacagc tgctcattgc ccccttcaaa   #            1150 gaggaggacg agtgggacag cccgcacatc gtcaggtact acgatgtcat   #            1200 gtctgatgag gaaatcgaga ggatcaagga gatcgcaaaa cctaaacttg   #            1250 cacgagccac cgttcgtgat cccaagacag gagtcctcac tgtcgccagc   #            1300 taccgggttt ccaaaagctc ctggctagag gaagatgatg accctgttgt   #            1350 ggcccgagta aatcgtcgga tgcagcatat cacagggtta acagtaaaga   #            1400 ctgcagaatt gttacaggtt gcaaattatg gagtgggagg acagtatgaa   #            1450 ccgcacttcg acttctctag gcgacctttt gacagcggcc tcaaaacaga   #            1500 ggggaatagg ttagcgacgt ttcttaacta catgagtgat gtagaagctg   #            1550 gtggtgccac cgtcttccct gatctggggg ctgcaatttg gcctaagaag   #            1600 ggtacagctg tgttctggta caacctcttg cggagcgggg aaggtgacta   #            1650 ccgaacaaga catgctgcct gccctgtgct tgtgggctgc aagtgggtct   #            1700 ccaataagtg gttccatgaa cgaggacagg agttcttgag accttgtgga   #            1750 tcaacagaag ttgactgaca tccttttctg tccttcccct tcctggtcct   #            1800 tcagcccatg tcaacgtgac agacaccttt gtatgttcct ttgtatgttc   #            1850 ctatcaggct gatttttgga gaaatgaatg tttgtctgga gcagagggag   #            1900 accatactag ggcgactcct gtgtgactga agtcccagcc cttccattca   #            1950 gcctgtgcca tccctggccc caaggctagg atcaaagtgg ctgcagcaga   #            2000 gttagctgtc tagcgcctag caaggtgcct ttgtacctca ggtgttttag   #            2050 gtgtgagatg tttcagtgaa ccaaagttct gataccttgt ttacatgttt   #            2100 gtttttatgg catttctatc tattgtggct ttaccaaaaa ataaaatgtc   #            2150 cctaccagaa aaaaaaaa              #                   #                   #2168 <210> SEQ ID NO 332 <211> LENGTH: 533 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 332 Met Lys Leu Trp Val Ser Ala Leu Leu Met Al #a Trp Phe Gly Val   1               5  #                 10  #                 15 Leu Ser Cys Val Gln Ala Glu Phe Phe Thr Se #r Ile Gly His Met                  20  #                 25  #                 30 Thr Asp Leu Ile Tyr Ala Glu Lys Glu Leu Va #l Gln Ser Leu Lys                  35  #                 40  #                 45 Glu Tyr Ile Leu Val Glu Glu Ala Lys Leu Se #r Lys Ile Lys Ser                  50  #                 55  #                 60 Trp Ala Asn Lys Met Glu Ala Leu Thr Ser Ly #s Ser Ala Ala Asp                  65  #                 70  #                 75 Ala Glu Gly Tyr Leu Ala His Pro Val Asn Al #a Tyr Lys Leu Val                  80  #                 85  #                 90 Lys Arg Leu Asn Thr Asp Trp Pro Ala Leu Gl #u Asp Leu Val Leu                  95  #                100  #                105 Gln Asp Ser Ala Ala Gly Phe Ile Ala Asn Le #u Ser Val Gln Arg                 110   #               115   #               120 Gln Phe Phe Pro Thr Asp Glu Asp Glu Ile Gl #y Ala Ala Lys Ala                 125   #               130   #               135 Leu Met Arg Leu Gln Asp Thr Tyr Arg Leu As #p Pro Gly Thr Ile                 140   #               145   #               150 Ser Arg Gly Glu Leu Pro Gly Thr Lys Tyr Gl #n Ala Met Leu Ser                 155   #               160   #               165 Val Asp Asp Cys Phe Gly Met Gly Arg Ser Al #a Tyr Asn Glu Gly                 170   #               175   #               180 Asp Tyr Tyr His Thr Val Leu Trp Met Glu Gl #n Val Leu Lys Gln                 185   #               190   #               195 Leu Asp Ala Gly Glu Glu Ala Thr Thr Thr Ly #s Ser Gln Val Leu                 200   #               205   #               210 Asp Tyr Leu Ser Tyr Ala Val Phe Gln Leu Gl #y Asp Leu His Arg                 215   #               220   #               225 Ala Leu Glu Leu Thr Arg Arg Leu Leu Ser Le #u Asp Pro Ser His                 230   #               235   #               240 Glu Arg Ala Gly Gly Asn Leu Arg Tyr Phe Gl #u Gln Leu Leu Glu                 245   #               250   #               255 Glu Glu Arg Glu Lys Thr Leu Thr Asn Gln Th #r Glu Ala Glu Leu                 260   #               265   #               270 Ala Thr Pro Glu Gly Ile Tyr Glu Arg Pro Va #l Asp Tyr Leu Pro                 275   #               280   #               285 Glu Arg Asp Val Tyr Glu Ser Leu Cys Arg Gl #y Glu Gly Val Lys                 290   #               295   #               300 Leu Thr Pro Arg Arg Gln Lys Arg Leu Phe Cy #s Arg Tyr His His                 305   #               310   #               315 Gly Asn Arg Ala Pro Gln Leu Leu Ile Ala Pr #o Phe Lys Glu Glu                 320   #               325   #               330 Asp Glu Trp Asp Ser Pro His Ile Val Arg Ty #r Tyr Asp Val Met                 335   #               340   #               345 Ser Asp Glu Glu Ile Glu Arg Ile Lys Glu Il #e Ala Lys Pro Lys                 350   #               355   #               360 Leu Ala Arg Ala Thr Val Arg Asp Pro Lys Th #r Gly Val Leu Thr                 365   #               370   #               375 Val Ala Ser Tyr Arg Val Ser Lys Ser Ser Tr #p Leu Glu Glu Asp                 380   #               385   #               390 Asp Asp Pro Val Val Ala Arg Val Asn Arg Ar #g Met Gln His Ile                 395   #               400   #               405 Thr Gly Leu Thr Val Lys Thr Ala Glu Leu Le #u Gln Val Ala Asn                 410   #               415   #               420 Tyr Gly Val Gly Gly Gln Tyr Glu Pro His Ph #e Asp Phe Ser Arg                 425   #               430   #               435 Arg Pro Phe Asp Ser Gly Leu Lys Thr Glu Gl #y Asn Arg Leu Ala                 440   #               445   #               450 Thr Phe Leu Asn Tyr Met Ser Asp Val Glu Al #a Gly Gly Ala Thr                 455   #               460   #               465 Val Phe Pro Asp Leu Gly Ala Ala Ile Trp Pr #o Lys Lys Gly Thr                 470   #               475   #               480 Ala Val Phe Trp Tyr Asn Leu Leu Arg Ser Gl #y Glu Gly Asp Tyr                 485   #               490   #               495 Arg Thr Arg His Ala Ala Cys Pro Val Leu Va #l Gly Cys Lys Trp                 500   #               505   #               510 Val Ser Asn Lys Trp Phe His Glu Arg Gly Gl #n Glu Phe Leu Arg                 515   #               520   #               525 Pro Cys Gly Ser Thr Glu Val Asp                 530 <210> SEQ ID NO 333 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 333 ccaggcacaa tttccaga              #                   #                   #  18 <210> SEQ ID NO 334 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 334 ggacccttct gtgtgccag              #                   #                   # 19 <210> SEQ ID NO 335 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 335 ggtctcaaga actcctgtc              #                   #                   # 19 <210> SEQ ID NO 336 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 336 acactcagca ttgcctggta cttg           #                   #                24 <210> SEQ ID NO 337 <211> LENGTH: 45 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 337 gggcacatga ctgacctgat ttatgcagag aaagagctgg tgcag    #                   #45 <210> SEQ ID NO 338 <211> LENGTH: 2789 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 338 gcagtattga gttttacttc ctcctctttt tagtggaaga cagaccataa   #              50 tcccagtgtg agtgaaattg attgtttcat ttattaccgt tttggctggg   #             100 ggttagttcc gacaccttca cagttgaaga gcaggcagaa ggagttgtga   #             150 agacaggaca atcttcttgg ggatgctggt cctggaagcc agcgggcctt   #             200 gctctgtctt tggcctcatt gaccccaggt tctctggtta aaactgaaag   #             250 cctactactg gcctggtgcc catcaatcca ttgatccttg aggctgtgcc   #             300 cctggggcac ccacctggca gggcctacca ccatgcgact gagctccctg   #             350 ttggctctgc tgcggccagc gcttcccctc atcttagggc tgtctctggg   #             400 gtgcagcctg agcctcctgc gggtttcctg gatccagggg gagggagaag   #             450 atccctgtgt cgaggctgta ggggagcgag gagggccaca gaatccagat   #             500 tcgagagctc ggctagacca aagtgatgaa gacttcaaac cccggattgt   #             550 cccctactac agggacccca acaagcccta caagaaggtg ctcaggactc   #             600 ggtacatcca gacagagctg ggctcccgtg agcggttgct ggtggctgtc   #             650 ctgacctccc gagctacact gtccactttg gccgtggctg tgaaccgtac   #             700 ggtggcccat cacttccctc ggttactcta cttcactggg cagcgggggg   #             750 cccgggctcc agcagggatg caggtggtgt ctcatgggga tgagcggccc   #             800 gcctggctca tgtcagagac cctgcgccac cttcacacac actttggggc   #             850 cgactacgac tggttcttca tcatgcagga tgacacatat gtgcaggccc   #             900 cccgcctggc agcccttgct ggccacctca gcatcaacca agacctgtac   #             950 ttaggccggg cagaggagtt cattggcgca ggcgagcagg cccggtactg   #            1000 tcatgggggc tttggctacc tgttgtcacg gagtctcctg cttcgtctgc   #            1050 ggccacatct ggatggctgc cgaggagaca ttctcagtgc ccgtcctgac   #            1100 gagtggcttg gacgctgcct cattgactct ctgggcgtcg gctgtgtctc   #            1150 acagcaccag gggcagcagt atcgctcatt tgaactggcc aaaaataggg   #            1200 accctgagaa ggaagggagc tcggctttcc tgagtgcctt cgccgtgcac   #            1250 cctgtctccg aaggtaccct catgtaccgg ctccacaaac gcttcagcgc   #            1300 tctggagttg gagcgggctt acagtgaaat agaacaactg caggctcaga   #            1350 tccggaacct gaccgtgctg acccccgaag gggaggcagg gctgagctgg   #            1400 cccgttgggc tccctgctcc tttcacacca cactctcgct ttgaggtgct   #            1450 gggctgggac tacttcacag agcagcacac cttctcctgt gcagatgggg   #            1500 ctcccaagtg cccactacag ggggctagca gggcggacgt gggtgatgcg   #            1550 ttggagactg ccctggagca gctcaatcgg cgctatcagc cccgcctgcg   #            1600 cttccagaag cagcgactgc tcaacggcta tcggcgcttc gacccagcac   #            1650 ggggcatgga gtacaccctg gacctgctgt tggaatgtgt gacacagcgt   #            1700 gggcaccggc gggccctggc tcgcagggtc agcctgctgc ggccactgag   #            1750 ccgggtggaa atcctaccta tgccctatgt cactgaggcc acccgagtgc   #            1800 agctggtgct gccactcctg gtggctgaag ctgctgcagc cccggctttc   #            1850 ctcgaggcgt ttgcagccaa tgtcctggag ccacgagaac atgcattgct   #            1900 caccctgttg ctggtctacg ggccacgaga aggtggccgt ggagctccag   #            1950 acccatttct tggggtgaag gctgcagcag cggagttaga gcgacggtac   #            2000 cctgggacga ggctggcctg gctcgctgtg cgagcagagg ccccttccca   #            2050 ggtgcgactc atggacgtgg tctcgaagaa gcaccctgtg gacactctct   #            2100 tcttccttac caccgtgtgg acaaggcctg ggcccgaagt cctcaaccgc   #            2150 tgtcgcatga atgccatctc tggctggcag gccttctttc cagtccattt   #            2200 ccaggagttc aatcctgccc tgtcaccaca gagatcaccc ccagggcccc   #            2250 cgggggctgg ccctgacccc ccctcccctc ctggtgctga cccctcccgg   #            2300 ggggctccta taggggggag atttgaccgg caggcttctg cggagggctg   #            2350 cttctacaac gctgactacc tggcggcccg agcccggctg gcaggtgaac   #            2400 tggcaggcca ggaagaggag gaagccctgg aggggctgga ggtgatggat   #            2450 gttttcctcc ggttctcagg gctccacctc tttcgggccg tagagccagg   #            2500 gctggtgcag aagttctccc tgcgagactg cagcccacgg ctcagtgaag   #            2550 aactctacca ccgctgccgc ctcagcaacc tggaggggct agggggccgt   #            2600 gcccagctgg ctatggctct ctttgagcag gagcaggcca atagcactta   #            2650 gcccgcctgg gggccctaac ctcattacct ttcctttgtc tgcctcagcc   #            2700 ccaggaaggg caaggcaaga tggtggacag atagagaatt gttgctgtat   #            2750 tttttaaata tgaaaatgtt attaaacatg tcttctgcc       #                   #  2789 <210> SEQ ID NO 339 <211> LENGTH: 772 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 339 Met Arg Leu Ser Ser Leu Leu Ala Leu Leu Ar #g Pro Ala Leu Pro   1               5  #                 10  #                 15 Leu Ile Leu Gly Leu Ser Leu Gly Cys Ser Le #u Ser Leu Leu Arg                  20  #                 25  #                 30 Val Ser Trp Ile Gln Gly Glu Gly Glu Asp Pr #o Cys Val Glu Ala                  35  #                 40  #                 45 Val Gly Glu Arg Gly Gly Pro Gln Asn Pro As #p Ser Arg Ala Arg                  50  #                 55  #                 60 Leu Asp Gln Ser Asp Glu Asp Phe Lys Pro Ar #g Ile Val Pro Tyr                  65  #                 70  #                 75 Tyr Arg Asp Pro Asn Lys Pro Tyr Lys Lys Va #l Leu Arg Thr Arg                  80  #                 85  #                 90 Tyr Ile Gln Thr Glu Leu Gly Ser Arg Glu Ar #g Leu Leu Val Ala                  95  #                100  #                105 Val Leu Thr Ser Arg Ala Thr Leu Ser Thr Le #u Ala Val Ala Val                 110   #               115   #               120 Asn Arg Thr Val Ala His His Phe Pro Arg Le #u Leu Tyr Phe Thr                 125   #               130   #               135 Gly Gln Arg Gly Ala Arg Ala Pro Ala Gly Me #t Gln Val Val Ser                 140   #               145   #               150 His Gly Asp Glu Arg Pro Ala Trp Leu Met Se #r Glu Thr Leu Arg                 155   #               160   #               165 His Leu His Thr His Phe Gly Ala Asp Tyr As #p Trp Phe Phe Ile                 170   #               175   #               180 Met Gln Asp Asp Thr Tyr Val Gln Ala Pro Ar #g Leu Ala Ala Leu                 185   #               190   #               195 Ala Gly His Leu Ser Ile Asn Gln Asp Leu Ty #r Leu Gly Arg Ala                 200   #               205   #               210 Glu Glu Phe Ile Gly Ala Gly Glu Gln Ala Ar #g Tyr Cys His Gly                 215   #               220   #               225 Gly Phe Gly Tyr Leu Leu Ser Arg Ser Leu Le #u Leu Arg Leu Arg                 230   #               235   #               240 Pro His Leu Asp Gly Cys Arg Gly Asp Ile Le #u Ser Ala Arg Pro                 245   #               250   #               255 Asp Glu Trp Leu Gly Arg Cys Leu Ile Asp Se #r Leu Gly Val Gly                 260   #               265   #               270 Cys Val Ser Gln His Gln Gly Gln Gln Tyr Ar #g Ser Phe Glu Leu                 275   #               280   #               285 Ala Lys Asn Arg Asp Pro Glu Lys Glu Gly Se #r Ser Ala Phe Leu                 290   #               295   #               300 Ser Ala Phe Ala Val His Pro Val Ser Glu Gl #y Thr Leu Met Tyr                 305   #               310   #               315 Arg Leu His Lys Arg Phe Ser Ala Leu Glu Le #u Glu Arg Ala Tyr                 320   #               325   #               330 Ser Glu Ile Glu Gln Leu Gln Ala Gln Ile Ar #g Asn Leu Thr Val                 335   #               340   #               345 Leu Thr Pro Glu Gly Glu Ala Gly Leu Ser Tr #p Pro Val Gly Leu                 350   #               355   #               360 Pro Ala Pro Phe Thr Pro His Ser Arg Phe Gl #u Val Leu Gly Trp                 365   #               370   #               375 Asp Tyr Phe Thr Glu Gln His Thr Phe Ser Cy #s Ala Asp Gly Ala                 380   #               385   #               390 Pro Lys Cys Pro Leu Gln Gly Ala Ser Arg Al #a Asp Val Gly Asp                 395   #               400   #               405 Ala Leu Glu Thr Ala Leu Glu Gln Leu Asn Ar #g Arg Tyr Gln Pro                 410   #               415   #               420 Arg Leu Arg Phe Gln Lys Gln Arg Leu Leu As #n Gly Tyr Arg Arg                 425   #               430   #               435 Phe Asp Pro Ala Arg Gly Met Glu Tyr Thr Le #u Asp Leu Leu Leu                 440   #               445   #               450 Glu Cys Val Thr Gln Arg Gly His Arg Arg Al #a Leu Ala Arg Arg                 455   #               460   #               465 Val Ser Leu Leu Arg Pro Leu Ser Arg Val Gl #u Ile Leu Pro Met                 470   #               475   #               480 Pro Tyr Val Thr Glu Ala Thr Arg Val Gln Le #u Val Leu Pro Leu                 485   #               490   #               495 Leu Val Ala Glu Ala Ala Ala Ala Pro Ala Ph #e Leu Glu Ala Phe                 500   #               505   #               510 Ala Ala Asn Val Leu Glu Pro Arg Glu His Al #a Leu Leu Thr Leu                 515   #               520   #               525 Leu Leu Val Tyr Gly Pro Arg Glu Gly Gly Ar #g Gly Ala Pro Asp                 530   #               535   #               540 Pro Phe Leu Gly Val Lys Ala Ala Ala Ala Gl #u Leu Glu Arg Arg                 545   #               550   #               555 Tyr Pro Gly Thr Arg Leu Ala Trp Leu Ala Va #l Arg Ala Glu Ala                 560   #               565   #               570 Pro Ser Gln Val Arg Leu Met Asp Val Val Se #r Lys Lys His Pro                 575   #               580   #               585 Val Asp Thr Leu Phe Phe Leu Thr Thr Val Tr #p Thr Arg Pro Gly                 590   #               595   #               600 Pro Glu Val Leu Asn Arg Cys Arg Met Asn Al #a Ile Ser Gly Trp                 605   #               610   #               615 Gln Ala Phe Phe Pro Val His Phe Gln Glu Ph #e Asn Pro Ala Leu                 620   #               625   #               630 Ser Pro Gln Arg Ser Pro Pro Gly Pro Pro Gl #y Ala Gly Pro Asp                 635   #               640   #               645 Pro Pro Ser Pro Pro Gly Ala Asp Pro Ser Ar #g Gly Ala Pro Ile                 650   #               655   #               660 Gly Gly Arg Phe Asp Arg Gln Ala Ser Ala Gl #u Gly Cys Phe Tyr                 665   #               670   #               675 Asn Ala Asp Tyr Leu Ala Ala Arg Ala Arg Le #u Ala Gly Glu Leu                 680   #               685   #               690 Ala Gly Gln Glu Glu Glu Glu Ala Leu Glu Gl #y Leu Glu Val Met                 695   #               700   #               705 Asp Val Phe Leu Arg Phe Ser Gly Leu His Le #u Phe Arg Ala Val                 710   #               715   #               720 Glu Pro Gly Leu Val Gln Lys Phe Ser Leu Ar #g Asp Cys Ser Pro                 725   #               730   #               735 Arg Leu Ser Glu Glu Leu Tyr His Arg Cys Ar #g Leu Ser Asn Leu                 740   #               745   #               750 Glu Gly Leu Gly Gly Arg Ala Gln Leu Ala Me #t Ala Leu Phe Glu                 755   #               760   #               765 Gln Glu Gln Ala Asn Ser Thr                 770 <210> SEQ ID NO 340 <211> LENGTH: 1572 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 340 cggagtggtg cgccaacgtg agaggaaacc cgtgcgcggc tgcgctttcc   #              50 tgtccccaag ccgttctaga cgcgggaaaa atgctttctg aaagcagctc   #             100 ctttttgaag ggtgtgatgc ttggaagcat tttctgtgct ttgatcacta   #             150 tgctaggaca cattaggatt ggtcatggaa atagaatgca ccaccatgag   #             200 catcatcacc tacaagctcc taacaaagaa gatatcttga aaatttcaga   #             250 ggatgagcgc atggagctca gtaagagctt tcgagtatac tgtattatcc   #             300 ttgtaaaacc caaagatgtg agtctttggg ctgcagtaaa ggagacttgg   #             350 accaaacact gtgacaaagc agagttcttc agttctgaaa atgttaaagt   #             400 gtttgagtca attaatatgg acacaaatga catgtggtta atgatgagaa   #             450 aagcttacaa atacgccttt gataagtata gagaccaata caactggttc   #             500 ttccttgcac gccccactac gtttgctatc attgaaaacc taaagtattt   #             550 tttgttaaaa aaggatccat cacagccttt ctatctaggc cacactataa   #             600 aatctggaga ccttgaatat gtgggtatgg aaggaggaat tgtcttaagt   #             650 gtagaatcaa tgaaaagact taacagcctt ctcaatatcc cagaaaagtg   #             700 tcctgaacag ggagggatga tttggaagat atctgaagat aaacagctag   #             750 cagtttgcct gaaatatgct ggagtatttg cagaaaatgc agaagatgct   #             800 gatggaaaag atgtatttaa taccaaatct gttgggcttt ctattaaaga   #             850 ggcaatgact tatcacccca accaggtagt agaaggctgt tgttcagata   #             900 tggctgttac ttttaatgga ctgactccaa atcagatgca tgtgatgatg   #             950 tatggggtat accgccttag ggcatttggg catattttca atgatgcatt   #            1000 ggttttctta cctccaaatg gttctgacaa tgactgagaa gtggtagaaa   #            1050 agcgtgaata tgatctttgt ataggacgtg tgttgtcatt atttgtagta   #            1100 gtaactacat atccaataca gctgtatgtt tctttttctt ttctaatttg   #            1150 gtggcactgg tataaccaca cattaaagtc agtagtacat ttttaaatga   #            1200 gggtggtttt tttctttaaa acacatgaac attgtaaatg tgttggaaag   #            1250 aagtgtttta agaataataa ttttgcaaat aaactattaa taaatattat   #            1300 atgtgataaa ttctaaatta tgaacattag aaatctgtgg ggcacatatt   #            1350 tttgctgatt ggttaaaaaa ttttaacagg tctttagcgt tctaagatat   #            1400 gcaaatgata tctctagttg tgaatttgtg attaaagtaa aacttttagc   #            1450 tgtgtgttcc ctttacttct aatactgatt tatgttctaa gcctccccaa   #            1500 gttccaatgg atttgccttc tcaaaatgta caactaagca actaaagaaa   #            1550 attaaagtga aagttgaaaa at            #                   #               1572 <210> SEQ ID NO 341 <211> LENGTH: 318 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 341 Met Leu Ser Glu Ser Ser Ser Phe Leu Lys Gl #y Val Met Leu Gly   1               5  #                 10  #                 15 Ser Ile Phe Cys Ala Leu Ile Thr Met Leu Gl #y His Ile Arg Ile                  20  #                 25  #                 30 Gly His Gly Asn Arg Met His His His Glu Hi #s His His Leu Gln                  35  #                 40  #                 45 Ala Pro Asn Lys Glu Asp Ile Leu Lys Ile Se #r Glu Asp Glu Arg                  50  #                 55  #                 60 Met Glu Leu Ser Lys Ser Phe Arg Val Tyr Cy #s Ile Ile Leu Val                  65  #                 70  #                 75 Lys Pro Lys Asp Val Ser Leu Trp Ala Ala Va #l Lys Glu Thr Trp                  80  #                 85  #                 90 Thr Lys His Cys Asp Lys Ala Glu Phe Phe Se #r Ser Glu Asn Val                  95  #                100  #                105 Lys Val Phe Glu Ser Ile Asn Met Asp Thr As #n Asp Met Trp Leu                 110   #               115   #               120 Met Met Arg Lys Ala Tyr Lys Tyr Ala Phe As #p Lys Tyr Arg Asp                 125   #               130   #               135 Gln Tyr Asn Trp Phe Phe Leu Ala Arg Pro Th #r Thr Phe Ala Ile                 140   #               145   #               150 Ile Glu Asn Leu Lys Tyr Phe Leu Leu Lys Ly #s Asp Pro Ser Gln                 155   #               160   #               165 Pro Phe Tyr Leu Gly His Thr Ile Lys Ser Gl #y Asp Leu Glu Tyr                 170   #               175   #               180 Val Gly Met Glu Gly Gly Ile Val Leu Ser Va #l Glu Ser Met Lys                 185   #               190   #               195 Arg Leu Asn Ser Leu Leu Asn Ile Pro Glu Ly #s Cys Pro Glu Gln                 200   #               205   #               210 Gly Gly Met Ile Trp Lys Ile Ser Glu Asp Ly #s Gln Leu Ala Val                 215   #               220   #               225 Cys Leu Lys Tyr Ala Gly Val Phe Ala Glu As #n Ala Glu Asp Ala                 230   #               235   #               240 Asp Gly Lys Asp Val Phe Asn Thr Lys Ser Va #l Gly Leu Ser Ile                 245   #               250   #               255 Lys Glu Ala Met Thr Tyr His Pro Asn Gln Va #l Val Glu Gly Cys                 260   #               265   #               270 Cys Ser Asp Met Ala Val Thr Phe Asn Gly Le #u Thr Pro Asn Gln                 275   #               280   #               285 Met His Val Met Met Tyr Gly Val Tyr Arg Le #u Arg Ala Phe Gly                 290   #               295   #               300 His Ile Phe Asn Asp Ala Leu Val Phe Leu Pr #o Pro Asn Gly Ser                 305   #               310   #               315 Asp Asn Asp <210> SEQ ID NO 342 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 342 tccccaagcc gttctagacg cgg            #                   #                23 <210> SEQ ID NO 343 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 343 ctggttcttc cttgcacg              #                   #                   #  18 <210> SEQ ID NO 344 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 344 gcccaaatgc cctaaggcgg tatacccc          #                   #             28 <210> SEQ ID NO 345 <211> LENGTH: 50 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 345 gggtgtgatg cttggaagca ttttctgtgc tttgatcact atgctaggac   #              50 <210> SEQ ID NO 346 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 346 gggatgcagg tggtgtctca tgggg           #                   #               25 <210> SEQ ID NO 347 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 347 ccctcatgta ccggctcc              #                   #                   #  18 <210> SEQ ID NO 348 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 348 ggattctaat acgactcact atagggctca gaaaagcgca acagagaa   #                48 <210> SEQ ID NO 349 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 349 ctatgaaatt aaccctcact aaagggatgt cttccatgcc aaccttc    #                47 <210> SEQ ID NO 350 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 350 ggattctaat acgactcact atagggcggc gatgtccact ggggctac   #                48 <210> SEQ ID NO 351 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 351 ctatgaaatt aaccctcact aaagggacga ggaagatggg cggatggt   #                48 <210> SEQ ID NO 352 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 352 ggattctaat acgactcact atagggcacc cacgcgtccg gctgctt    #                47 <210> SEQ ID NO 353 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 353 ctatgaaatt aaccctcact aaagggacgg gggacaccac ggaccaga   #                48 <210> SEQ ID NO 354 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 354 ggattctaat acgactcact atagggcttg ctgcggtttt tgttcctg   #                48 <210> SEQ ID NO 355 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 355 ctatgaaatt aaccctcact aaagggagct gccgatccca ctggtatt   #                48 <210> SEQ ID NO 356 <211> LENGTH: 46 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 356 ggattctaat acgactcact atagggcgga tcctggccgg cctctg    #                 46 <210> SEQ ID NO 357 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 357 ctatgaaatt aaccctcact aaagggagcc cgggcatggt ctcagtta   #                48 <210> SEQ ID NO 358 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 358 ggattctaat acgactcact atagggcggg aagatggcga ggaggag    #                47 <210> SEQ ID NO 359 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 359 ctatgaaatt aaccctcact aaagggacca aggccacaaa cggaaatc   #                48 <210> SEQ ID NO 360 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 360 ggattctaat acgactcact atagggctgt gctttcattc tgccagta   #                48 <210> SEQ ID NO 361 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 361 ctatgaaatt aaccctcact aaagggaggg tacaattaag gggtggat   #                48 <210> SEQ ID NO 362 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 362 ggattctaat acgactcact atagggcccg cctcgctcct gctcctg    #                47 <210> SEQ ID NO 363 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 363 ctatgaaatt aaccctcact aaagggagga ttgccgcgac cctcacag   #                48 <210> SEQ ID NO 364 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 364 ggattctaat acgactcact atagggcccc tcctgccttc cctgtcc    #                47 <210> SEQ ID NO 365 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 365 ctatgaaatt aaccctcact aaagggagtg gtggccgcga ttatctgc   #                48 <210> SEQ ID NO 366 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 366 ggattctaat acgactcact atagggcgca gcgatggcag cgatgagg   #                48 <210> SEQ ID NO 367 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 367 ctatgaaatt aaccctcact aaagggacag acggggcaga gggagtg    #                47 <210> SEQ ID NO 368 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 368 ggattctaat acgactcact atagggccag gaggcgtgag gagaaac    #                47 <210> SEQ ID NO 369 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 369 ctatgaaatt aaccctcact aaagggaaag acatgtcatc gggagtgg   #                48 <210> SEQ ID NO 370 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 370 ggattctaat acgactcact atagggccgg gtggaggtgg aacagaaa   #                48 <210> SEQ ID NO 371 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 371 ctatgaaatt aaccctcact aaagggacac agacagagcc ccatacgc   #                48 <210> SEQ ID NO 372 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 372 ggattctaat acgactcact atagggccag ggaaatccgg atgtctc    #                47 <210> SEQ ID NO 373 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 373 ctatgaaatt aaccctcact aaagggagta aggggatgcc accgagta   #                48 <210> SEQ ID NO 374 <211> LENGTH: 47 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 374 ggattctaat acgactcact atagggccag ctacccgcag gaggagg    #                47 <210> SEQ ID NO 375 <211> LENGTH: 48 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 375 ctatgaaatt aaccctcact aaagggatcc caggtgatga ggtccaga   #                48 <210> SEQ ID NO 376 <211> LENGTH: 997 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 376 cccacgcgtc cgatcttacc aacaaaacac tcctgaggag aaagaaagag   #              50 agggagggag agaaaaagag agagagagaa acaaaaaacc aaagagagag   #             100 aaaaaatgaa ttcatctaaa tcatctgaaa cacaatgcac agagagagga   #             150 tgcttctctt cccaaatgtt cttatggact gttgctggga tccccatcct   #             200 atttctcagt gcctgtttca tcaccagatg tgttgtgaca tttcgcatct   #             250 ttcaaacctg tgatgagaaa aagtttcagc tacctgagaa tttcacagag   #             300 ctctcctgct acaattatgg atcaggttca gtcaagaatt gttgtccatt   #             350 gaactgggaa tattttcaat ccagctgcta cttcttttct actgacacca   #             400 tttcctgggc gttaagttta aagaactgct cagccatggg ggctcacctg   #             450 gtggttatca actcacagga ggagcaggaa ttcctttcct acaagaaacc   #             500 taaaatgaga gagtttttta ttggactgtc agaccaggtt gtcgagggtc   #             550 agtggcaatg ggtggacggc acacctttga caaagtctct gagcttctgg   #             600 gatgtagggg agcccaacaa catagctacc ctggaggact gtgccaccat   #             650 gagagactct tcaaacccaa ggcaaaattg gaatgatgta acctgtttcc   #             700 tcaattattt tcggatttgt gaaatggtag gaataaatcc tttgaacaaa   #             750 ggaaaatctc tttaagaaca gaaggcacaa ctcaaatgtg taaagaagga   #             800 agagcaagaa catggccaca cccaccgccc cacacgagaa atttgtgcgc   #             850 tgaacttcaa aggacttcat aagtatttgt tactctgata caaataaaaa   #             900 taagtagttt taaatgttaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa   #             950 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaa    #               997 <210> SEQ ID NO 377 <211> LENGTH: 219 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 377 Met Asn Ser Ser Lys Ser Ser Glu Thr Gln Cy #s Thr Glu Arg Gly   1               5  #                 10  #                 15 Cys Phe Ser Ser Gln Met Phe Leu Trp Thr Va #l Ala Gly Ile Pro                  20  #                 25  #                 30 Ile Leu Phe Leu Ser Ala Cys Phe Ile Thr Ar #g Cys Val Val Thr                  35  #                 40  #                 45 Phe Arg Ile Phe Gln Thr Cys Asp Glu Lys Ly #s Phe Gln Leu Pro                  50  #                 55  #                 60 Glu Asn Phe Thr Glu Leu Ser Cys Tyr Asn Ty #r Gly Ser Gly Ser                  65  #                 70  #                 75 Val Lys Asn Cys Cys Pro Leu Asn Trp Glu Ty #r Phe Gln Ser Ser                  80  #                 85  #                 90 Cys Tyr Phe Phe Ser Thr Asp Thr Ile Ser Tr #p Ala Leu Ser Leu                  95  #                100  #                105 Lys Asn Cys Ser Ala Met Gly Ala His Leu Va #l Val Ile Asn Ser                 110   #               115   #               120 Gln Glu Glu Gln Glu Phe Leu Ser Tyr Lys Ly #s Pro Lys Met Arg                 125   #               130   #               135 Glu Phe Phe Ile Gly Leu Ser Asp Gln Val Va #l Glu Gly Gln Trp                 140   #               145   #               150 Gln Trp Val Asp Gly Thr Pro Leu Thr Lys Se #r Leu Ser Phe Trp                 155   #               160   #               165 Asp Val Gly Glu Pro Asn Asn Ile Ala Thr Le #u Glu Asp Cys Ala                 170   #               175   #               180 Thr Met Arg Asp Ser Ser Asn Pro Arg Gln As #n Trp Asn Asp Val                 185   #               190   #               195 Thr Cys Phe Leu Asn Tyr Phe Arg Ile Cys Gl #u Met Val Gly Ile                 200   #               205   #               210 Asn Pro Leu Asn Lys Gly Lys Ser Leu                 215 <210> SEQ ID NO 378 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 378 ttcagcttct gggatgtagg g            #                   #                   #21 <210> SEQ ID NO 379 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic Oligonucleotide Pr #obe <400> SEQUENCE: 379 tattcctacc atttcacaaa tccg           #                   #                24 <210> SEQ ID NO 380 <211> LENGTH: 49 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 380 ggaggactgt gccaccatga gagactcttc aaacccaagg caaaattgg   #               49 <210> SEQ ID NO 381 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 381 gcagattttg aggacagcca cctcca           #                   #              26 <210> SEQ ID NO 382 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 382 ggccttgcag acaaccgt              #                   #                   #  18 <210> SEQ ID NO 383 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 383 cagactgagg gagatccgag a            #                   #                   #21 <210> SEQ ID NO 384 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 384 cagctgccct tccccaacca             #                   #                   # 20 <210> SEQ ID NO 385 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 385 catcaagcgc ctctacca              #                   #                   #  18 <210> SEQ ID NO 386 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 386 cacaaactcg aactgcttct g            #                   #                   #21 <210> SEQ ID NO 387 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 387 gggccatcac agctccct              #                   #                   #  18 <210> SEQ ID NO 388 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 388 gggatgtggt gaacacagaa ca            #                   #                 22 <210> SEQ ID NO 389 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 389 tgccagctgc atgctgccag tt            #                   #                 22 <210> SEQ ID NO 390 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 390 cagaaggatg tcccgtggaa             #                   #                   # 20 <210> SEQ ID NO 391 <211> LENGTH: 17 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 391 gccgctgtcc actgcag              #                   #                   #   17 <210> SEQ ID NO 392 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 392 gacggcatcc tcagggccac a            #                   #                   #21 <210> SEQ ID NO 393 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 393 atgtcctcca tgcccacgcg             #                   #                   # 20 <210> SEQ ID NO 394 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 394 gagtgcgaca tcgagagctt             #                   #                   # 20 <210> SEQ ID NO 395 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 395 ccgcagcctc agtgatga              #                   #                   #  18 <210> SEQ ID NO 396 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 396 gaagagcaca gctgcagatc c            #                   #                   #21 <210> SEQ ID NO 397 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 397 gaggtgtcct ggctttggta gt            #                   #                 22 <210> SEQ ID NO 398 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 398 cctctggcgc ccccactcaa             #                   #                   # 20 <210> SEQ ID NO 399 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 399 ccaggagagc tggcgatg              #                   #                   #  18 <210> SEQ ID NO 400 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 400 gcaaattcag ggctcactag aga            #                   #                23 <210> SEQ ID NO 401 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 401 cacagagcat ttgtccatca gcagttcag          #                   #            29 <210> SEQ ID NO 402 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 402 ggcagagact tccagtcact ga            #                   #                 22 <210> SEQ ID NO 403 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 403 gccaagggtg gtgttagata gg            #                   #                 22 <210> SEQ ID NO 404 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 404 caggccccct tgatctgtac ccca           #                   #                24 <210> SEQ ID NO 405 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 405 gggacgtgct tctacaagaa cag            #                   #                23 <210> SEQ ID NO 406 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 406 caggcttaca atgttatgat cagaca           #                   #              26 <210> SEQ ID NO 407 <211> LENGTH: 31 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 407 tattcagagt tttccattgg cagtgccagt t         #                   #                   #     31 <210> SEQ ID NO 408 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 408 tctacatcag cctctctgcg c            #                   #                   #21 <210> SEQ ID NO 409 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 409 cgatcttctc cacccaggag cgg            #                   #                23 <210> SEQ ID NO 410 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 410 gccaggcctc acattcgt              #                   #                   #  18 <210> SEQ ID NO 411 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 411 ctccctgaat ggcagcctga gca            #                   #                23 <210> SEQ ID NO 412 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 412 aggtgtttat taagggccta cgct           #                   #                24 <210> SEQ ID NO 413 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 413 cagagcagag ggtgccttg              #                   #                   # 19 <210> SEQ ID NO 414 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 414 tggcggagtc ccctcttggc t            #                   #                   #21 <210> SEQ ID NO 415 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 415 ccctgtttcc ctatgcatca ct            #                   #                 22 <210> SEQ ID NO 416 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 416 tcaacccctg accctttcct a            #                   #                   #21 <210> SEQ ID NO 417 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 417 ggcaggggac aagccatctc tcct           #                   #                24 <210> SEQ ID NO 418 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 418 gggactgaac tgccagcttc             #                   #                   # 20 <210> SEQ ID NO 419 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 419 gggccctaac ctcattacct tt            #                   #                 22 <210> SEQ ID NO 420 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 420 tgtctgcctc agccccagga agg            #                   #                23 <210> SEQ ID NO 421 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Synthetic oligonucleotide pr #obe <400> SEQUENCE: 421 tctgtccacc atcttgcctt g            #                   #                   #21 <210> SEQ ID NO 422 <211> LENGTH: 3554 <212> TYPE: DNA <213> ORGANISM: Homo Sapien <400> SEQUENCE: 422 gggactacaa gccgcgccgc gctgccgctg gcccctcagc aaccctcgac   #              50 atggcgctga ggcggccacc gcgactccgg ctctgcgctc ggctgcctga   #             100 cttcttcctg ctgctgcttt tcaggggctg cctgataggg gctgtaaatc   #             150 tcaaatccag caatcgaacc ccagtggtac aggaatttga aagtgtggaa   #             200 ctgtcttgca tcattacgga ttcgcagaca agtgacccca ggatcgagtg   #             250 gaagaaaatt caagatgaac aaaccacata tgtgtttttt gacaacaaaa   #             300 ttcagggaga cttggcgggt cgtgcagaaa tactggggaa gacatccctg   #             350 aagatctgga atgtgacacg gagagactca gccctttatc gctgtgaggt   #             400 cgttgctcga aatgaccgca aggaaattga tgagattgtg atcgagttaa   #             450 ctgtgcaagt gaagccagtg acccctgtct gtagagtgcc gaaggctgta   #             500 ccagtaggca agatggcaac actgcactgc caggagagtg agggccaccc   #             550 ccggcctcac tacagctggt atcgcaatga tgtaccactg cccacggatt   #             600 ccagagccaa tcccagattt cgcaattctt ctttccactt aaactctgaa   #             650 acaggcactt tggtgttcac tgctgttcac aaggacgact ctgggcagta   #             700 ctactgcatt gcttccaatg acgcaggctc agccaggtgt gaggagcagg   #             750 agatggaagt ctatgacctg aacattggcg gaattattgg gggggttctg   #             800 gttgtccttg ctgtactggc cctgatcacg ttgggcatct gctgtgcata   #             850 cagacgtggc tacttcatca acaataaaca ggatggagaa agttacaaga   #             900 acccagggaa accagatgga gttaactaca tccgcactga cgaggagggc   #             950 gacttcagac acaagtcatc gtttgtgatc tgagacccgc ggtgtggctg   #            1000 agagcgcaca gagcgcacgt gcacatacct ctgctagaaa ctcctgtcaa   #            1050 ggcagcgaga gctgatgcac tcggacagag ctagacactc attcagaagc   #            1100 ttttcgtttt ggccaaagtt gaccactact cttcttactc taacaagcca   #            1150 catgaataga agaattttcc tcaagatgga cccggtaaat ataaccacaa   #            1200 ggaagcgaaa ctgggtgcgt tcactgagtt gggttcctaa tctgtttctg   #            1250 gcctgattcc cgcatgagta ttagggtgat cttaaagagt ttgctcacgt   #            1300 aaacgcccgt gctgggccct gtgaagccag catgttcacc actggtcgtt   #            1350 cagcagccac gacagcacca tgtgagatgg cgaggtggct ggacagcacc   #            1400 agcagcgcat cccggcggga acccagaaaa ggcttcttac acagcagcct   #            1450 tacttcatcg gcccacagac accaccgcag tttcttctta aaggctctgc   #            1500 tgatcggtgt tgcagtgtcc attgtggaga agctttttgg atcagcattt   #            1550 tgtaaaaaca accaaaatca ggaaggtaaa ttggttgctg gaagagggat   #            1600 cttgcctgag gaaccctgct tgtccaacag ggtgtcagga tttaaggaaa   #            1650 accttcgtct taggctaagt ctgaaatggt actgaaatat gcttttctat   #            1700 gggtcttgtt tattttataa aattttacat ctaaattttt gctaaggatg   #            1750 tattttgatt attgaaaaga aaatttctat ttaaactgta aatatattgt   #            1800 catacaatgt taaataacct atttttttaa aaaagttcaa cttaaggtag   #            1850 aagttccaag ctactagtgt taaattggaa aatatcaata attaagagta   #            1900 ttttacccaa ggaatcctct catggaagtt tactgtgatg ttccttttct   #            1950 cacacaagtt ttagcctttt tcacaaggga actcatactg tctacacatc   #            2000 agaccatagt tgcttaggaa acctttaaaa attccagtta agcaatgttg   #            2050 aaatcagttt gcatctcttc aaaagaaacc tctcaggtta gctttgaact   #            2100 gcctcttcct gagatgacta ggacagtctg tacccagagg ccacccagaa   #            2150 gccctcagat gtacatacac agatgccagt cagctcctgg ggttgcgcca   #            2200 ggcgcccccg ctctagctca ctgttgcctc gctgtctgcc aggaggccct   #            2250 gccatccttg ggccctggca gtggctgtgt cccagtgagc tttactcacg   #            2300 tggcccttgc ttcatccagc acagctctca ggtgggcact gcagggacac   #            2350 tggtgtcttc catgtagcgt cccagctttg ggctcctgta acagacctct   #            2400 ttttggttat ggatggctca caaaataggg cccccaatgc tatttttttt   #            2450 ttttaagttt gtttaattat ttgttaagat tgtctaaggc caaaggcaat   #            2500 tgcgaaatca agtctgtcaa gtacaataac atttttaaaa gaaaatggat   #            2550 cccactgttc ctctttgcca cagagaaagc acccagacgc cacaggctct   #            2600 gtcgcatttc aaaacaaacc atgatggagt ggcggccagt ccagcctttt   #            2650 aaagaacgtc aggtggagca gccaggtgaa aggcctggcg gggaggaaag   #            2700 tgaaacgcct gaatcaaaag cagttttcta attttgactt taaatttttc   #            2750 atccgccgga gacactgctc ccatttgtgg ggggacatta gcaacatcac   #            2800 tcagaagcct gtgttcttca agagcaggtg ttctcagcct cacatgccct   #            2850 gccgtgctgg actcaggact gaagtgctgt aaagcaagga gctgctgaga   #            2900 aggagcactc cactgtgtgc ctggagaatg gctctcacta ctcaccttgt   #            2950 ctttcagctt ccagtgtctt gggtttttta tactttgaca gctttttttt   #            3000 aattgcatac atgagactgt gttgactttt tttagttatg tgaaacactt   #            3050 tgccgcaggc cgcctggcag aggcaggaaa tgctccagca gtggctcagt   #            3100 gctccctggt gtctgctgca tggcatcctg gatgcttagc atgcaagttc   #            3150 cctccatcat tgccaccttg gtagagaggg atggctcccc accctcagcg   #            3200 ttggggattc acgctccagc ctccttcttg gttgtcatag tgatagggta   #            3250 gccttattgc cccctcttct tataccctaa aaccttctac actagtgcca   #            3300 tgggaaccag gtctgaaaaa gtagagagaa gtgaaagtag agtctgggaa   #            3350 gtagctgcct ataactgaga ctagacggaa aaggaatact cgtgtatttt   #            3400 aagatatgaa tgtgactcaa gactcgaggc cgatacgagg ctgtgattct   #            3450 gcctttggat ggatgttgct gtacacagat gctacagact tgtactaaca   #            3500 caccgtaatt tggcatttgt ttaacctcat ttataaaagc ttcaaaaaaa   #            3550 ccca                  #                   #                   #           3554 <210> SEQ ID NO 423 <211> LENGTH: 310 <212> TYPE: PRT <213> ORGANISM: Homo Sapien <400> SEQUENCE: 423 Met Ala Leu Arg Arg Pro Pro Arg Leu Arg Le #u Cys Ala Arg Leu   1               5  #                 10  #                 15 Pro Asp Phe Phe Leu Leu Leu Leu Phe Arg Gl #y Cys Leu Ile Gly                  20  #                 25  #                 30 Ala Val Asn Leu Lys Ser Ser Asn Arg Thr Pr #o Val Val Gln Glu                  35  #                 40  #                 45 Phe Glu Ser Val Glu Leu Ser Cys Ile Ile Th #r Asp Ser Gln Thr                  50  #                 55  #                 60 Ser Asp Pro Arg Ile Glu Trp Lys Lys Ile Gl #n Asp Glu Gln Thr                  65  #                 70  #                 75 Thr Tyr Val Phe Phe Asp Asn Lys Ile Gln Gl #y Asp Leu Ala Gly                  80  #                 85  #                 90 Arg Ala Glu Ile Leu Gly Lys Thr Ser Leu Ly #s Ile Trp Asn Val                  95  #                100  #                105 Thr Arg Arg Asp Ser Ala Leu Tyr Arg Cys Gl #u Val Val Ala Arg                 110   #               115   #               120 Asn Asp Arg Lys Glu Ile Asp Glu Ile Val Il #e Glu Leu Thr Val                 125   #               130   #               135 Gln Val Lys Pro Val Thr Pro Val Cys Arg Va #l Pro Lys Ala Val                 140   #               145   #               150 Pro Val Gly Lys Met Ala Thr Leu His Cys Gl #n Glu Ser Glu Gly                 155   #               160   #               165 His Pro Arg Pro His Tyr Ser Trp Tyr Arg As #n Asp Val Pro Leu                 170   #               175   #               180 Pro Thr Asp Ser Arg Ala Asn Pro Arg Phe Ar #g Asn Ser Ser Phe                 185   #               190   #               195 His Leu Asn Ser Glu Thr Gly Thr Leu Val Ph #e Thr Ala Val His                 200   #               205   #               210 Lys Asp Asp Ser Gly Gln Tyr Tyr Cys Ile Al #a Ser Asn Asp Ala                 215   #               220   #               225 Gly Ser Ala Arg Cys Glu Glu Gln Glu Met Gl #u Val Tyr Asp Leu                 230   #               235   #               240 Asn Ile Gly Gly Ile Ile Gly Gly Val Leu Va #l Val Leu Ala Val                 245   #               250   #               255 Leu Ala Leu Ile Thr Leu Gly Ile Cys Cys Al #a Tyr Arg Arg Gly                 260   #               265   #               270 Tyr Phe Ile Asn Asn Lys Gln Asp Gly Glu Se #r Tyr Lys Asn Pro                 275   #               280   #               285 Gly Lys Pro Asp Gly Val Asn Tyr Ile Arg Th #r Asp Glu Glu Gly                 290   #               295   #               300 Asp Phe Arg His Lys Ser Ser Phe Val Ile                 305   #               310 

What is claimed is:
 1. An isolated nucleic acid comprising: (a) a nucleic acid sequence encoding the polypeptide shown in FIG. 104 (SEQ ID NO:292); (b) a nucleic acid sequence encoding the polypeptide shown in FIG. 104 (SEQ ID NO:292), lacking its associated signal peptide; (c) a nucleic acid sequence encoding the extracellular domain of the polypeptide shown in FIG. 104 (SEQ ID NO:292); (d) the full-length coding sequence of the nucleic acid sequence shown in FIG. 103 (SEQ ID NO:291); or (e) the full-length coding sequence of the cDNA deposited under ATCC accession number
 209439. 2. The isolated nucleic acid of claim 1 comprising a nucleic acid sequence encoding the polypeptide shown in FIG. 104 (SEQ ID NO:292).
 3. The isolated nucleic acid of claim 1 comprising a nucleic acid sequence encoding the polypeptide shown in FIG. 104 (SEQ ID NO:292), lacking its associated signal peptide.
 4. The isolated nucleic acid of claim 1 comprising a nucleic acid sequence encoding the extracellular domain of the polypeptide shown in FIG. 104 (SEQ ID NO:292).
 5. The isolated nucleic acid of claim 1 comprising the nucleic acid sequence shown in FIG. 103 (SEQ ID NO:291).
 6. The isolated nucleic acid of claim 1 comprising the full-length coding sequence of the nucleic acid sequence shown in FIG. 103 (SEQ ID NO:291).
 7. The isolated nucleic acid of claim 1 comprising the full-length coding sequence of the cDNA deposited under ATCC accession number
 209439. 8. A vector comprising the nucleic acid of claim
 1. 9. The vector of claim 8, wherein said nucleic acid is operably linked to control sequences recognized by a host cell transformed with the vector.
 10. A host cell comprising the vector of claim
 8. 11. The host cell of claim 10, wherein said cell is a CHO cell, an E. coli or a yeast cell. 